ORCID Profile
0000-0002-5929-4387
Current Organisation
Monash University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biomedical Engineering | Nanotechnology | Medical Physiology Not Elsewhere Classified | Biomaterials | Mechanical Engineering | Biotechnology Not Elsewhere Classified | Biomedical Engineering Not Elsewhere Classified | Mechanical Engineering | Fluid Physics | Biophysics
ANZSRC Socio-Economic Objective (SEO)
Urogenital system and disorders | Public health not elsewhere classified | Health related to ageing | Preventive medicine | Cardiovascular system and diseases | Prevention—biologicals (e.g. vaccines) | Diagnostics | Biological sciences |
Related Links
Publications
Blunted natriuretic response to saline loading in sheep with hypertensive kidney disease following radiofrequency catheter-based renal denervation
Publisher: Springer Science and Business Media LLC
Date: 20-07-2021
DOI: 10.1038/S41598-021-94221-5
Abstract: Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD.
Role of the sympathetic nervous system and its modulation in renal hypertension
Publisher: Frontiers Media SA
Date: 29-03-2018
Blood flow in the glomerular capillary network
Publisher: Elsevier
Date: 2000
In the arms of Morpheus
Publisher: American Physiological Society
Date: 15-01-2012
Brief Early Life Angiotensin-Converting Enzyme Inhibition Offers Renoprotection in Sheep with a Solitary Functioning Kidney at 8 Months of Age
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2022
Abstract: Children born with a solitary functioning kidney (SFK) can develop kidney injury as a consequence of glomerular hyperfiltration. Angiotensin-converting enzyme inhibitors (ACEis) reduce BP and are renoprotective in adults. Our study demonstrates that treatment with ACEi early in life (between weeks 4 and 8 after birth) in sheep born with a SFK prevents albuminuria and reduces glomerular hyperfiltration, thus maintaining renal functional reserve, 6 months after treatment withdrawal. Further, improvements in kidney function were associated with increased nitric oxide bioavailability. This study suggests ACEi for 1 month early in life may improve the trajectory for the development of kidney disease in in iduals born with SFK. Children born with a solitary functioning kidney (SFK) are predisposed to develop hypertension and kidney injury. Glomerular hyperfiltration and hypertrophy contribute to the pathophysiology of kidney injury. Angiotensin-converting enzyme inhibition (ACEi) can mitigate hyperfiltration and may be therapeutically beneficial in reducing progression of kidney injury in those with an SFK. SFK was induced in male sheep fetuses at 100 days gestation (term=150 days). Between 4 and 8 weeks of age, SFK lambs received enalapril (SFK+ACEi 0.5mg/kg per day, once daily, orally) or vehicle (SFK). At 8 months, we examined BP, basal kidney function, renal functional reserve (RFR GFR response to combined amino acid and dopamine infusion), GFR response to nitric oxide synthase (NOS) inhibition, and basal nitric oxide (NO) bioavailability (basal urinary total nitrate and nitrite [NOx]). SFK+ACEi prevented albuminuria and resulted in lower basal GFR (16%), higher renal blood flow (approximately 22%), and lower filtration fraction (approximately 35%), but similar BP, compared with vehicle-treated SFK sheep. Together with greater recruitment of RFR (approximately 14%) in SFK+ACEi than SFK animals, this indicates a reduction in glomerular hyperfiltration–mediated kidney dysfunction. During NOS inhibition, the decrease in GFR (approximately 14%) was greater among SFK+ACEi than among SFK animals. Increased (approximately 85%) basal urinary total NOx in SFK+ACEi compared with SFK animals indicates elevated NO bioavailability likely contributed to improvements in kidney function and prevention of albuminuria. Brief and early ACEi in SFK is associated with reduced glomerular hyperfiltration–mediated kidney disease up to 8 months of age in a sheep model.
Response to Can the Study of Female Rats Help Our Understanding of Women?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Bezlotoxumab prevents extraintestinal organ damage induced by Clostridioides difficile infection.
Publisher: Informa UK Limited
Date: 31-08-2022
Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/192567
Abstract: Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT 2 R). However, the role of vascular AT 2 R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult ( ~ 17 weeks) and aged ( ~ 19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT 1 R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT 2 R antagonist, PD123319. In a separate group of animals, the specific Mas R antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure ( ~ 15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT 2 R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT 2 R blockade or Mas R blockade. At the same time, AT 2 R, Mas R, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT 2 R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT 2 R and Mas R.
Renal Denervation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2018
Editorial: Function of renal sympathetic nerves
Publisher: Frontiers Media SA
Date: 28-08-2017
Ontogeny of Placental Structural Development and Expression of the Renin-Angiotensin System and 11β-HSD2 Genes in the Rabbit
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.PLACENTA.2009.04.006
Abstract: Common pregnancy complications are associated with impaired placental development. This study aimed to characterise the ontogeny of structural correlates of rabbit placental function, its expression of genes encoding components of the renin-angiotensin system (RAS), as well as 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) mRNA since these are known to be expressed by the placenta and are associated with pregnancy complications, including preecl sia and intrauterine programming. Placentae were collected at gestational age (GA) 14, 21 and 28 (term=32 days). Gene expression was analysed using real time PCR and placental structures were quantified via image analyses. The volume densities and volumes of trophoblast, fetal capillaries, maternal blood space, surface density and surface area of trophoblast all progressively increased, while the arithmetic mean barrier thickness of trophoblast decreased across gestation. Maternal plasma renin activity (PRA) was positively correlated with volumes of trophoblast and maternal blood space, surface density and surface area of trophoblast. Placental renin mRNA declined ( downward arrow62% P<0.01) across gestation and was negatively correlated with maternal PRA (GA0), fetal and placental weights, placental angiotensin type 1 and 2 receptors (AT(1)R and AT(2)R) mRNA and volume of trophoblast. AT(1)R mRNA expression was increased by 92% (P<0.001) across gestation. AT2R mRNA expression was approximately 81% (P<0.01) greater at GA14 compared to GA21. Placental 11beta-HSD2 mRNA expression was approximately 74% greater (P<0.01) at GA21 than GA14, but by GA28 was similar to that at GA14. These data show that changes in placental gene expression are associated with key events in placental and fetal development, indicating that the rabbit provides a good model for investigations of pregnancy perturbations that alter the RAS or programme the fetus.
Intrarenal haemodynamic and glomerular responses to inhibition of nitric oxide formation in rabbits.
Publisher: Wiley
Date: 15-02-1994
DOI: 10.1113/JPHYSIOL.1994.SP020057
Abstract: 1. The renal effects of inhibiting nitric oxide (NO) formation using N-nitro-L-arginine (NOLA, 20 mg kg-1) were examined using micropuncture techniques in pentobarbitone-anaesthetized rabbits. 2. Renal vascular resistance doubled from 2.7 +/- 0.5 to 5.0 +/- 1.1 mmHg ml-1 min-1 after NOLA (P < 0.01), with similar percentage increases in both pre- (149 +/- 38%, P < 0.01) and postglomerular (158 +/- 42%, P < 0.01) resistance. 3. Glomerular capillary pressure rose from 33 +/- 1 to 40 +/- 1 mmHg after NOLA (P < 0.01) but despite this, glomerular filtration rate (GFR) and single nephron glomerular filtration rate did not significantly change. 4. Blood pressure increased 18 +/- 1 mmHg (P < 0.001) within 10 min of NOLA administration and remained near this level for the next 90 min. 5. The glomerular ultrafiltration coefficient (Kf) decreased significantly from 0.085 +/- 0.022 to 0.035 +/- 0.006 nl s-1 mmHg-1 (P < 0.05). 6. Urine flow and sodium excretion increased markedly (26 +/- 9 to 337 +/- 102 microliters min-1 and 5 +/- 2 to 342 +/- 12 mumol min-1 respectively, (P < 0.001)) and sodium fractional excretion rose from 1.0 +/- 0.3 to 8.0 +/- 2.2% (P < 0.01). 7. Thus, administration of NOLA to rabbits caused vasoconstriction of both pre- and postglomerular vessels, diuresis and natriuresis without significant change in GFR, and a reduction in Kf. The results suggest that NO may play an important role in the regulation of renal haemodynamics and glomerular function.
Antihypertensives and Antibiotics: Impact on Intestinal Dysfunction and Hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2023
DOI: 10.1161/HYPERTENSIONAHA.122.20073
Abstract: Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis. However, the mechanisms underlying this restoration of gut structure and function remain largely unknown. In this review, we examine current knowledge supporting a role for impaired intestinal epithelial permeability in hypertension, focusing on electrolyte movement, the renin-angiotensin-aldosterone system, and the restorative effects of orally administered antihypertensive medications and antibiotics. Further work is required to determine if the association between intestinal dysfunction and hypertension is causal. This is a rapidly evolving field, with intestinal dysfunction and dysbiosis representing an area that may be exploited to improve treatment of hypertension and cardiovascular disease.
Serelaxin and the AT2 Receptor Agonist CGP42112 Evoked a Similar, Nonadditive, Cardiac Antifibrotic Effect in High Salt-Fed Mice That Were Refractory to Candesartan Cilexetil
Publisher: American Chemical Society (ACS)
Date: 23-01-2020
Maternal Obesity: Bad for Baby's Future
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Response to Letters Regarding Article, “Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep”
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-10-2015
The angiotensin type 2 receptor weighs in on obesity: a promising therapeutic target?
Publisher: Springer Science and Business Media LLC
Date: 16-02-2012
DOI: 10.1038/HR.2012.22
AW-APSH-1: TARGETING WINDOWS OF PLASTICITY TO PREVENT HYPERTENSION.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2023
Induction of hyperglycemia in adult intrauterine growth-restricted rats: Effects on renal function
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPRENAL.00564.2010
Abstract: Intrauterine growth restriction (IUGR) leads to a reduction in nephron endowment at birth and is linked to renal dysfunction in adulthood. The aim of the present study was to determine whether kidneys of IUGR rat offspring are more vulnerable to a secondary insult of hyperglycemia. IUGR was induced in Wistar-Kyoto rats by maternal protein restriction. At 24 wk of age, diabetes was induced in male IUGR and non-IUGR offspring by streptozotocin injection insulin was injected daily to maintain blood glucose levels at either a mild (7–10 mmol/l n=8/group) or a moderate (10–15 mmol/l n=8/group) level. At 32 wk of age, renal function was assessed using ultrasound and [ 3 H]inulin and [ 14 C]para-aminohippurate clearance techniques. Conscious mean arterial blood pressure and heart rate were unchanged in IUGR offspring. Relative kidney length was increased significantly in IUGR offspring, and renal function was altered significantly of importance, there was a significant increase in filtration fraction, indicative of glomerular hyperfiltration. Induction of hyperglycemia led to marked impairment of renal function. However, the response to hyperglycemia was not different between IUGR and non-IUGR offspring. Maintaining blood glucose levels at a mild hyperglycemic level led to marked improvement in all measures of renal function in IUGR and non-IUGR offspring. In conclusion, while the IUGR offspring showed evidence of hyperfiltration, the response to hyperglycemia was similar in IUGR and non-IUGR kidneys in adulthood. Importantly, maintaining blood glucose levels at a mild hyperglycemic level markedly attenuated the renal dysfunction associated with diabetes, even in IUGR offspring.
Role of the kidney in the fetal programming of adult cardiovascular disease: An update
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.COPH.2014.12.010
Abstract: It is well established that an adverse in utero environment can impinge upon fetal development and place the offspring on a track leading to future cardiovascular disease. Significantly, this may occur in the absence of any outward manifestations at birth. In this brief review, we focus on potential renal mechanisms that lead to adaptations in glomerular and tubular function that initiate hypertension of developmental origin and examine potential therapeutic interventions. This report updates recent data in this field.
Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats
Publisher: Portland Press Ltd.
Date: 04-2020
DOI: 10.1042/CS20200153
Abstract: Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro7-Ang III. In both male and female rats, acute systemic administration of β-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro7-Ang III administered. Moreover, intra-renal administration of β-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.
New physiological targets within the kidney for antihypertensive therapy
Publisher: Bentham Science Publishers Ltd.
Date: 03-2005
Postnatal growth and the tracking of blood pressure
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2008
Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement
Publisher: The Endocrine Society
Date: 11-03-2021
Abstract: In May 2014, the National Institutes of Health (NIH) stated its intent to “require applicants to consider sex as a biological variable (SABV) in the design and analysis of NIH-funded research involving animals and cells.” Since then, proposed research plans that include animals routinely state that both sexes/genders will be used however, in many instances, researchers and reviewers are at a loss about the issue of sex differences. Moreover, the terms sex and gender are used interchangeably by many researchers, further complicating the issue. In addition, the sex or gender of the researcher might influence study outcomes, especially those concerning behavioral studies, in both animals and humans. The act of observation may change the outcome (the “observer effect”) and any experimental manipulation, no matter how well-controlled, is subject to it. This is nowhere more applicable than in physiology and behavior. The sex of established cultured cell lines is another issue, in addition to aneuploidy chromosomal numbers can change as cells are passaged. Additionally, culture medium contains steroids, growth hormone, and insulin that might influence expression of various genes. These issues often are not taken into account, determined, or even considered. Issues pertaining to the “sex” of cultured cells are beyond the scope of this Statement. However, we will discuss the factors that influence sex and gender in both basic research (that using animal models) and clinical research (that involving human subjects), as well as in some areas of science where sex differences are routinely studied. Sex differences in baseline physiology and associated mechanisms form the foundation for understanding sex differences in diseases pathology, treatments, and outcomes. The purpose of this Statement is to highlight lessons learned, caveats, and what to consider when evaluating data pertaining to sex differences, using 3 areas of research as ex les it is not intended to serve as a guideline for research design.
Physiology and Pathophysiology of Compensatory Adaptations of a Solitary Functioning Kidney
Publisher: Frontiers Media SA
Date: 26-06-2020
Chronic maternal hypertension affects placental gene expression and differentiation in rabbits
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2010
DOI: 10.1097/HJH.0B013E3283369F1E
Abstract: Previously, we have shown that adult offspring from hypertensive rabbits develop hypertension. We aimed to determine the effects of mild (+15 mmHg) and moderate (+25 mmHg) increases in maternal blood pressure and plasma renin activity on placental differentiation and expression of components of the renin-angiotensin system and 11[beta]-hydroxysteroid dehydrogenase type 2 mRNA in rabbits. Placentas were collected from normotensive (sham), mild (2-kidney-1-cellophane wrapped 2K-1W) and moderate (2-kidney-2-cellophane wrapped 2K-2W) hypertensive groups at gestational age of 14, 21 and 28 days. Placental gene expression was quantified by reverse transcriptase-PCR, and morphometry was assessed by videoimage analyses of placental sections. Fetal weight was similar between groups across gestation. In the 2K-1W group at gestational age day 14, fetal-to-placental weight ratio was increased (approximately 34%) as were volumes of fetal capillaries ([up arrow]56%) and maternal blood space at gestational age day 21 ([up arrow]55%) compared with sham (all P < 0.05). In the 2K-2W group, fetal-to-placental weight ratio was increased at gestational age day 21 (approximately 25% P < 0.01) with an accompanying reduction in placental weight, and at gestational age day 28, volume density of fetal capillaries was increased (approximately 22% P < 0.05). Placental renin mRNA was lower in both the 2K-1W (approximately 88%) and 2K-2W (approximately 98%) groups at gestational age day 28 (all P < 0.01). Placental 11[beta]-hydroxysteroid dehydrogenase type 2 mRNA was lower in the 2K-1W (approximately 36%) and 2K-2W (approximately 31%) groups at gestational age day 14 and greater (approximately 36%) in the 2K-2W group at gestational age day 21 (all P < 0.01). Associations between placental AT1R and AT2R mRNA and placental differentiation were disturbed by hypertension. Mild and moderate maternal hypertension differentially alters placental structure and gene expression that may affect placental functional capacity and contribute to programming of hypertension in offspring.
Sex-specific differences in hypertension and associated cardiovascular disease
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
Abstract: Although intrinsic mechanisms that regulate arterial blood pressure (BP) are similar in men and women, marked variations exist at the molecular, cellular and tissue levels. These physiological disparities between the sexes likely contribute to differences in disease onset, susceptibility, prevalence and treatment responses. Key systems that are important in the development of hypertension and cardiovascular disease (CVD), including the sympathetic nervous system, the renin-angiotensin-aldosterone system and the immune system, are differentially activated in males and females. Biological age also contributes to sexual dimorphism, as premenopausal women experience a higher degree of cardioprotection than men of similar age. Furthermore, sex hormones such as oestrogen and testosterone as well as sex chromosome complement likely contribute to sex differences in BP and CVD. At the cellular level, differences in cell senescence pathways may contribute to increased longevity in women and may also limit organ damage caused by hypertension. In addition, many lifestyle and environmental factors - such as smoking, alcohol consumption and diet - may influence BP and CVD in a sex-specific manner. Evidence suggests that cardioprotection in women is lost under conditions of obesity and type 2 diabetes mellitus. Treatment strategies for hypertension and CVD that are tailored according to sex could lead to improved outcomes for affected patients.
Renal Denervation in Combination With Angiotensin Receptor Blockade Prolongs Blood Pressure Trough During Hemorrhage
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2022
DOI: 10.1161/HYPERTENSIONAHA.121.18354
Abstract: Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.
Insulin-regulated aminopeptidase deficiency impairs cardiovascular adaptations and placental development during pregnancy
Publisher: Portland Press Ltd.
Date: 12-2020
DOI: 10.1042/CS20201233
Abstract: Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preecl sia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wild-type and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ∼40 bpm lower in IRAP knockout females compared with wild-type females. The increase in heart rate across gestation was greater in IRAP knockout females than wild-type females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ∼45% less than wild-type mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrate that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy.
Extracting Information From Sympathetic Nerve Traffic in Gestational Hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2023
Epochs in the depressor/pressor balance of the renin-angiotensin system.
Publisher: Portland Press Ltd.
Date: 04-2016
DOI: 10.1042/CS20150939
Abstract: The renin–angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1–7) [Ang(1–7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor ressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life.
The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent
Publisher: American Physiological Society
Date: 2012
DOI: 10.1152/AJPREGU.00256.2011
Abstract: The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT 2 R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT 2 R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg −1 ·min −1 sc) or saline. MAP significantly decreased in females treated with ANG II (−10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (−6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.
Anti-fibrotic potential of AT2 receptor agonists
Publisher: Frontiers Media SA
Date: 31-08-2017
Reduced sensitivity of the renal vasculature to angiotensin II in young rats: The role of the angiotensin type 2 receptor
Publisher: Springer Science and Business Media LLC
Date: 13-08-2014
DOI: 10.1038/PR.2014.121
Abstract: The angiotensin type-2 receptor (AT2R) opposes the vasoconstrictor actions of angiotensin II (AngII) mediated through the angiotensin type-1 receptor (AT1R). Renal AT2R levels are high during fetal life, but decrease significantly during postnatal maturation. To provide insight into the functional role of the AT2R in the kidney during postnatal development, we investigated the effects of AT2R antagonism on cardiovascular responses to AngII in young and adult male rats. In anesthetized 3- and 6-wk-old male Sprague-Dawley rats, mean arterial pressure (MAP) and renal blood flow (RBF) were measured in response to AngII in the presence of vehicle treatment or AT2R blockade with PD123319. The pressor effect of AngII and associated reduction in RBF were significantly less in 3-wk- than 6-wk-old rats. AT2R blockade potentiated the reduction in RBF in response to AngII in 3-wk-old rats only. In young rats, the AT2R modulates the response to AngII, blunting renal vasoconstriction. This effect is attenuated with age in association with a developmental reduction in renal AT2R expression. These findings may have implications for the development of novel therapies that target the renin-angiotensin system for the improvement of renal function in term and, in particular, preterm infants.
Connecting Generations of Scientists in the Council on Hypertension Through Harriet Dustan
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2021
RENAL VENOUS WEDGE PRESSURE IN RENAL WRAP HYPERTENSION IN RABBITS
Publisher: Wiley
Date: 08-1989
DOI: 10.1111/J.1440-1681.1989.TB01621.X
Abstract: 1. Renal cellophane wrapping to produce hypertension causes thickening of the capsule of the kidney. To determine whether this compresses the kidney, deep renal vein wedge pressure was measured as an estimate of tissue pressure in anaesthetized rabbits 1 month after cellophane wrapping (n = 5) or a sham operation (n = 3). 2. Renal vein wedge pressure was 18.3 +/- 2.0 mmHg in hypertensive rabbits and 8.4 +/- 1.1 mmHg in the sham-operated rabbits. 3. Arterial pressure was raised or lowered with angiotensin II or glyceryl trinitrate, respectively. Arterial and wedge pressures were approximately linearly related and, at any given arterial pressure, wedge pressure was approximately 8 mmHg higher in the cellophane-wrapped kidney than in the kidney of the sham-operated group. 4. These results, showing that renal wedge pressure is elevated in renal wrap rabbits, indicate that the kidneys are compressed, probably by the thickened renal capsule. This may explain the increased renal vascular resistance seen in this form of hypertension.
Differential sympathetic response to lesion-induced chronic kidney disease in rabbits.
Publisher: Elsevier BV
Date: 10-2020
Glomerular ultrafiltration in rabbits with superficial glomeruli
Publisher: Springer Science and Business Media LLC
Date: 10-1991
DOI: 10.1007/BF00371101
Abstract: Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke. Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV(1)) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV(1) 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm(2), p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm(2), p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p = 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV(1)/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils). Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.
Perinatal Programming of Arterial Pressure
Publisher: Springer International Publishing
Date: 2018
Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment
Publisher: American Physiological Society
Date: 12-2011
DOI: 10.1152/AJPRENAL.00463.2011
Abstract: Fetal uninephrectomy (uni-x) in male sheep at 100 days of gestation (term = 150 days) reduces overall nephron endowment without affecting birth weight. Offspring have a lower glomerular filtration rate (GFR) and elevated mean arterial pressure (MAP) at 6 mo of age. This study investigated whether this reduction in renal function was associated with impaired urine-concentrating ability at 6 mo of age and exacerbated with ageing (4 yr) and examined response to 1) nonpressor dose of exogenous arginine vasopressin (AVP 0.2 μg·kg −1 ·h −1 iv) and 2) 30 h of water deprivation. Basal MAP was higher in uni-x animals at both ages, and became further elevated with age compared with the sham group (elevation in MAP with age sham: ∼4 mmHg, uni-x: 9 mmHg, P group × age 0.01). GFR declined with ageing in both groups with the decrease being greater with age in the uni-x group (further 26%, P group × age 0.001). In response to AVP infusion, urine osmolality increased in both treatment groups this response was significantly lower in the uni-x animals and became further reduced with ageing. Uni-x animals had reduced renal expression of vasopressin-2 receptor and aquaporin-2 at both ages ( P 0.01). The increase in plasma AVP levels in response to dehydration was similar between the treatment groups, suggesting the urine-concentrating defect was associated with these renal gene changes rather than defects in AVP secretion. Renal insufficiency due to a low-nephron endowment increases the risk of hypertension and chronic renal disease and may incur greater vulnerability to physiological challenges such as water deprivation as observed in the uni-x animals.
Loss of a kidney during fetal life: long-term consequences and lessons learned
Publisher: American Physiological Society
Date: 15-04-2014
DOI: 10.1152/AJPRENAL.00666.2013
Abstract: Epidemiological studies reveal that children born with a solitary functioning kidney (SFK) have a greater predisposition to develop renal insufficiency and hypertension in early adulthood. A congenital SFK is present in patients with unilateral renal agenesis or unilateral multicystic kidney dysplasia, leading to both structural and functional adaptations in the remaining kidney, which act to mitigate the reductions in glomerular filtration rate and sodium excretion that would otherwise ensue. To understand the mechanisms underlying the early development of renal insufficiency in children born with a SFK, we established a model of fetal uninephrectomy (uni-x) in sheep, a species that similar to humans complete nephrogenesis before birth. This model results in a 30% reduction in nephron number rather than 50%, due to compensatory nephrogenesis in the remaining kidney. Similar to children with a congenital SFK, uni-x sheep demonstrate a progressive increase in arterial pressure and a loss of renal function with aging. This review summarizes the compensatory changes in renal hemodynamics and tubular sodium handling that drive impairments in renal function and highlights the existence of sex differences in the functional adaptations following the loss of a kidney during fetal life.
Relaxin contributes to the regulation of arterial pressure in adult female mice.
Publisher: Portland Press Ltd.
Date: 28-11-2017
DOI: 10.1042/CS20171225
Abstract: Relaxin is increasingly being recognized as a potent vasodilatory and antifibrotic hormone. Given that relaxin is present in the circulation during the luteal phase of the menstrual cycle and during pregnancy, when arterial pressure is lowest in women, relaxin may contribute to the relative cardiovascular protection observed in premenopausal women as compared with age-matched men and postmenopausal women. In the present study, we investigated the contribution of relaxin to the normal regulation of arterial pressure in adult female and male mice and during pregnancy. Mean arterial pressure (MAP) was measured via radiotelemetry in 14-week-old male and female wild-type (WT C67BL/6xSv129) and relaxin knockout (KO) mice. Thereafter, female mice were time-mated with a (non-telemetered) male of the same genotype and MAP was measured throughout gestation. Basal MAP was ∼10 mmHg lower in WT females than males (P& .05). Relaxin deficiency increased basal MAP in females (P& .05 vs WT female), but not males. As expected, MAP decreased during gestation in WT mice. Conversely, in relaxin KO mice, arterial pressure increased during mid and late gestation (P& .05 as compared with WT). Moreover, relaxin deficiency impaired gestational weight gain and reduced litter size. This is the first study to (i) demonstrate that relaxin contributes to the sexual dimorphism of arterial pressure in mice and (ii) document the changes in the arterial pressure profile of pregnant relaxin KO mice. Understanding the mechanisms that underlie the regulation of arterial pressure in premenopausal females may uncover new strategies to treat hypertension in women (non-pregnant and pregnant) and men.
Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension
Publisher: American Physiological Society
Date: 02-2007
DOI: 10.1152/AJPREGU.00458.2006
Abstract: Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1W, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group ( n = 9). Mean arterial blood pressure was increased by ∼20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (P G 0.001). Plasma renin activity (PRA P G 0.05) and aldosterone (P G 0.05) levels were increased during gestation in the 2K-1W, but not the 2K-2W mothers. Birth weight was increased by ∼20% in offspring of both groups of hypertensive mothers (P T 0.001), though this was associated with a reduction in litter size. Renal noradrenaline content was increased (∼40%, P 0.05) at 5 wk of age in female 2K-1W offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers however, glomerular tuft volume was reduced in female 2K-2W offspring ( P 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1W model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension.
Lack of contribution of P2X receptors to neurally mediated vasoconstriction in the rabbit kidney in vivo
Publisher: Wiley
Date: 31-01-2006
DOI: 10.1111/J.1748-1716.2006.01526.X
Abstract: The contribution of adenosine triphosphate (ATP) to the neural control of regional renal perfusion in vivo remains unknown. We therefore examined whether P2X receptors mediate renal vascular responses to electrical stimulation of the renal nerves (RNS) in pentobarbitone anaesthetized rabbits. Responses to RNS were tested before and during renal arterial infusion of alpha,beta-methylene ATP (alpha,beta-mATP, 7-56 microg kg(-1) min(-1)) to desensitize P2X1 receptors. RNS consisted of 3 min trains at graded frequencies and short trains of RNS (4-32 pulses). Three-minute trains of RNS reduced renal blood flow (RBF), cortical laser Doppler flux (CLDF), and medullary LDF (MLDF) by -90 +/- 3%, -89 +/- 3% and -31 +/- 11%, respectively, at 4 Hz. MLDF was reduced less than CLDF or RBF. During short train RNS, RBF, CLDF and MLDF were reduced by -22 +/- 2%, -15 +/- 2% and -12 +/- 2%, respectively, for 32 s at 1 Hz. CLDF and MLDF were reduced to a similar extent. Infusion of alpha,beta-mATP induced transient reductions in RBF, CLDF and MLDF, but within 5 min these variables had recovered to control levels. Vascular responses to RNS were not significantly altered by alpha,beta-mATP treatment. In the rabbit kidney in vivo, alpha,beta-mATP-sensitive receptors mediate vasoconstriction and reduce perfusion in both cortical and medullary vascular beds. However, these receptors do not mediate neurally induced reductions in renal perfusion.
Relaxin Attenuates Organ Fibrosis via an Angiotensin Type 2 Receptor Mechanism in Aged Hypertensive Female Rats
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
Abstract: Relaxin attenuates tissue fibrosis in an organ- and age-specific manner. The antifibrotic actions of relaxin are mediated via an angiotensin type 2 receptor mechanism. Relaxin replacement therapy is a potential antifibrotic for cardiovascular and kidney disease in postmenopausal women. The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT 2 R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via AT 2 R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection via an AT 2 R-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs). In 6-month-old (6MO) and 15-month-old ([15MO] reproductively senescent) female SHRSP, systolic BP (SBP), GFR, and proteinuria were measured before and after 4 weeks of treatment with vehicle (Veh), RLX (0.5 mg/kg per day s.c.), or RLX+PD123319 (AT 2 R antagonist 3 mg/kg per day s.c.). Aortic endothelium–dependent relaxation and fibrosis of the kidney, heart, and aorta were assessed. In 6MO SHRSP, RLX significantly enhanced GFR by approximately 25% ( P =0.001) and reduced cardiac fibrosis ( P =0.01) as compared with vehicle-treated counterparts. These effects were abolished or blunted by PD123319 coadministration. In 15MO females, RLX reduced interstitial renal ( P =0.02) and aortic ( P =0.003) fibrosis and lowered SBP (13±3 mm Hg P =0.04) relative to controls. These effects were also blocked by PD123319 cotreatment (all P =0.05 versus RLX treatment alone). RLX also markedly improved vascular function by approximately 40% ( P .001) in 15MO SHRSP, but this was not modulated by PD123319 cotreatment. The antifibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats to a great extent via an AT 2 R-mediated mechanism.
Renal effects of atrial natriuretic peptide in conscious rabbits with renal wrap hypertension
Publisher: Informa UK Limited
Date: 1989
DOI: 10.3109/10641968909035291
Abstract: Atrial natriuretic peptide (ANP, 2 micrograms/min) was infused intravenously into rabbits four weeks after renal wrap or sham operation. Mean arterial pressure (MAP) averaged 132 +/- 4 mmHg in the renal wrapped rabbits and 89 +/- 3 mmHg in the sham rabbits, and glomerular filtration rate (GFR) was significantly lower in the hypertensive rabbits (6.2 +/- 1.0 ml/min) than in sham rabbits (8.9 +/- 0.7 ml/min). In sham rabbits, ANP caused a significant diuresis, natriuresis and increase in GFR. Enalapril pretreatment blunted these responses. In the hypertensive rabbits, ANP reduced mean arterial pressure but did not cause significant diuresis or natriuresis or change in GFR. Enalapril pretreatment did not significantly alter this response to ANP. In separate experiments, nitroprusside was infused to lower arterial pressure in hypertensive rabbits by a similar amount to that achieved with ANP and this reduced GFR, sodium and urine excretion rates. Thus ANP maintained GFR and sodium excretion in hypertensive rabbits compared to an equihypotensive dose of nitroprusside. In summary, ANP did not cause natriuresis or diuresis in renal wrapped kidneys at a dose which was effective in normal kidneys, but did maintain GFR, sodium and water excretion rates, compared to an equally hypotensive dose of nitroprusside.
"The more I learn, the more I realize how much I don't know." - The role of the renal nerves in hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
New insights on glomerular hyperfiltration: a Japanese autopsy study
Publisher: American Society for Clinical Investigation
Date: 05-10-2017
SEX‐DIFFERENCES IN CIRCADIAN BLOOD PRESSURE VARIATIONS IN RESPONSE TO CHRONIC ANGIOTENSIN II INFUSION IN RATS
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1440-1681.2008.04884.X
Abstract: 1. The aim of this study was to investigate the effect of chronic angiotensin II (AngII) infusion on the circadian rhythms of arterial blood pressure, heart rate (HR) and locomotor activity (ACT) in male and female rats. 2. Radiotelemetry probes were implanted into the aorta in male and female rats and allowed 10 days for recovery. Control levels for mean arterial pressure (MAP), HR and ACT were recorded for 3 days, then AngII (400 ng/kg per min s.c. via osmotic minipump) or vehicle (saline) was infused for 10 days (n = 6 per group). Further recordings of MAP, HR and ACT were made during days 8, 9 and 10 of the infusion period. 3. In response to AngII infusion, night and day-time MAP increased significantly in female (18 +/- 2 mmHg 28 +/- 7 mmHg) and male (27 +/- 4 mmHg 30 +/- 3 mmHg) rats, respectively. The degree of elevation in MAP in response to AngII was attenuated in the females during the night period (P(sex) < 0.05) but not the day (P(sex) = 0.2). Control night-day differences in MAP, HR and ACT averaged 7 +/- 1 mmHg, 58 +/- 5 b.p.m. and 30 +/- 4 units in the female and 6 +/- 1 mmHg, 43 +/- 3 b.p.m. (P(sex) < 0.05) and 14 +/- 2 units (P(sex) < 0.05) in male rats, respectively. AngII infusion disrupted MAP circadian rhythm in female (-4 +/- 2 mmHg) and male rats (1 +/- 2 mmHg P(treat) < 0.01), but did not affect heart rate or locomotor activity. 4. In conclusion, sex differences in the circadian rhythm of heart rate and locomotor activity, but not arterial pressure exist under basal conditions. Circulating AngII modulated the circadian rhythm of MAP in female and male rats but not heart rate or locomotor activity. These findings have important implications for our understanding of circadian blood pressure rhythms in states of activation of the renin angiotensin system.
Chronic low alcohol intake during pregnancy programs sex-specific cardiovascular deficits in rats
Publisher: Springer Science and Business Media LLC
Date: 22-04-2019
Gender Differences in Pressure-Natriuresis and Renal Autoregulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2010
DOI: 10.1161/HYPERTENSIONAHA.110.166827
Abstract: Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT 2 R) in pressure-natriuresis in male and female rats because AT 2 R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT 2 R antagonist-treated (PD123319 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats ( P .001). AT 2 R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male ( P .01) and female ( P .01) rats to a similar extent. In females, AT 2 R blockade also reduced the lower end of the autoregulatory range of renal blood flow ( P .05) and glomerular filtration rate ( P .01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT 2 R blockade. We found that AT 2 R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males ( P .05). In conclusion, the AT 2 R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT 2 R in renal autoregulation was evident in females, which may be a direct vascular AT 2 R effect.
Unmasking the potential of the angiotensin AT2 receptor as a therapeutic target in hypertension in men and women: What we know and what we still need to find out
Publisher: Wiley
Date: 29-07-2000
Abstract: Major sex differences exist in the development and progression of hypertension and cardiovascular disease. Prior to menopause, women have lower arterial pressure and, furthermore, are protected from hypertension and cardiovascular disease relative to age-matched men. However, after menopause this cardiovascular protection in women is lost. These sex differences have been linked to sexual dimorphism in the physiological mechanisms that regulate arterial pressure, including the renin-angiotensin system (RAS), which can also impact on the male and female response to different therapeutic approaches. This suggests that antihypertensive regimens need to be tailored according to sex. Newly discovered components of the RAS have emerged in recent years, allowing us to look beyond the classical RAS for novel therapeutic targets for hypertension. In this context, it is now well established that the angiotensin AT2 receptor (AT2 R) elicits depressor and natriuretic effects and that these effects are greater in females due to enhanced AT2 R levels modulated by oestrogen. In light of knowledge that AT2 R expression is regulated by oestrogen and that the prevalence of hypertension and cardiovascular risk is greater in women after menopause, AT2 R agonist therapy may represent an innovative therapeutic approach to treat hypertension. Consequently, understanding how ageing and changes in the sex hormone balance influence the RAS is vital if we are to evaluate the potential of the AT2 R as a therapeutic target in women and also in men.
Renal Denervation Promotes Atherosclerosis in Hypertensive Apolipoprotein E-Deficient Mice Infused with Angiotensin II.
Publisher: Frontiers Media SA
Date: 13-04-2017
Increased Cardiovascular and Renal Risk Is Associated with Low Nephron Endowment in Aged Females: An Ovine Model of Fetal Unilateral Nephrectomy
Publisher: Public Library of Science (PLoS)
Date: 03-08-2012
Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/RD13133
Abstract: A developmental insult that restricts growth in the first generation has the potential to program disease in subsequent generations. The aim of this study was to ascertain transgenerational growth and cardio–renal effects, via the maternal line, in a rat model of utero–placental insufficiency. Bilateral uterine vessel ligation or sham surgery (offspring termed first generation F1 Restricted and Control, respectively) was performed in WKY rats. F1 Restricted and Control females were mated with normal males to produce second generation (F2) offspring (Restricted and Control) studied from fetal (embryonic Day 20) to adult (12 months) life. F2 Restricted male and female fetuses had reduced (P 0.05) nephron number (down 15–22%) but this deficit was not sustained postnatally and levels were similar to Controls at Day 35. F2 Restricted males, but not females, developed elevated (+16 mmHg, P 0.05) systolic blood pressure at 6 months of age, which was sustained to 9 months. This was not explained by alterations to intra-renal or plasma components of the renin–angiotensin system. In a rat model of utero–placental insufficiency, we report alterations to F2 kidney development and sex-specific adult hypertension. This study demonstrates that low birthweight can have far-reaching effects that extend into the next generation.
Role of inflammation and the angiotensin type 2 receptor in the regulation of arterial pressure during pregnancy in mice
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
DOI: 10.1161/HYPERTENSIONAHA.114.03189
Abstract: During normal pregnancy the renin–angiotensin system is activated, yet pregnant women are resistant to the pressor effects of angiotensin II. Our aim was to determine the role of the angiotensin type 2 receptor (AT 2 R) in the regulation of arterial pressure, natriuresis, and immune cell infiltration during pregnancy. Mean arterial pressure was measured via telemetry, and flow cytometry was used to enumerate immune cell infiltration in 14-week-old wild-type and AT 2 R knockout mice during gestation. In wild-type mice, mean arterial pressure decreased during gestation, reaching a nadir at gestational day 9 (–6±2 mm Hg) and returned to near preconception levels during late gestation. In AT 2 R-deficient mice, the midgestational decrease in mean arterial pressure was absent. Furthermore, mean arterial pressure was significantly increased during late gestation compared with wild-type mice (≈10 mm Hg). As expected, circulating immune cell activation was suppressed during pregnancy. However, this response was absent in AT 2 R-deficient mice. While renal immune cell infiltration was similar between the genotypes, there was a significant T cell phenotypic switch toward a proinflammatory T-helper 1 phenotype in AT 2 R-deficient mice. These data indicate that the AT 2 R plays an important role in arterial pressure regulation and may modulate T cell activation and renal cytokine production during pregnancy. Therefore, deficits in AT 2 R expression may contribute to pregnancy-induced hypertension and thus represents a potential therapeutic target.
Renal Nitric Oxide Deficiency and Chronic Kidney Disease in Young Sheep Born with a Solitary Functioning Kidney
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26777
Abstract: Previously, we demonstrated that renal hemodynamic responses to nitric oxide (NO) inhibition were attenuated in aged, hypertensive sheep born with a solitary functioning kidney (SFK). NO is an important regulator of renal function, particularly, in the postnatal period. We hypothesized that the onset of renal dysfunction and hypertension in in iduals with a SFK is associated with NO deficiency early in life. In this study, renal and cardiovascular responses to L-NAME infusion (N w -nitro-L-arginine methyl ester) were examined in 6-month old lambs born with a SFK, induced by fetal unilateral nephrectomy (uni-x). Renal responses to L-NAME were attenuated in uni-x sheep with the fall in glomerular filtration rate (GFR) and urinary sodium excretion (U Na V) being less in the uni-x compared to sham lambs (%ΔGFR −41 ± 3 vs −54 ± 4: P = 0.03, %ΔU Na V −48 ± 5 vs −76 ± 3, P = 0.0008). 24 hour-basal urinary nitrate and nitrite (NOx) excretion was less in the uni-x animals compared to the sham (NOx excretion μM/min/kg sham: 57 ± 7 uni-x: 38 ± 4, P = 0.02). L-NAME treatment reduced urinary NOx to undetectable levels in both groups. A reduction in NO bioavailability in early life may contribute to the initiation of glomerular and tubular dysfunction that promotes development and progression of hypertension in offspring with a congenital nephron deficit, including those with a SFK.
Renal Deafferentation Prevents Progression of Hypertension and Changes to Sympathetic Reflexes in a Rabbit Model of Chronic Kidney Disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
DOI: 10.1161/HYPERTENSIONAHA.121.17037
Abstract: There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P .001), while RSNA (43%) and total norepinephrine spillover (28%) were elevated in CKD compared with sham (both P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.
Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 16-06-2022
Differential neural control of glomerular ultrafiltration
Publisher: Wiley
Date: 05-2004
DOI: 10.1111/J.1440-1681.2004.04002.X
Abstract: 1. The renal nerves constrict the renal vasculature, causing decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Whether renal haemodynamics are influenced by changes in renal nerve activity within the physiological range is a matter of debate. 2. We have identified two morphologically distinct populations of nerves within the kidney, which are differentially distributed to the renal afferent and efferent arterioles. Type I nerves almost exclusively innervate the afferent arteriole whereas type II nerves are distributed equally on the afferent and efferent arterioles. We have also demonstrated that type II nerves are immunoreactive for neuropeptide Y, whereas type I nerves are not. 3. This led us to hypothesize that, in the kidney, distinct populations of nerves innervate specific effector tissues and that these nerves may be selectively activated, setting the basis for the differential neural control of GFR. In physiological studies, we demonstrated that differential changes in glomerular capillary pressure occurred in response to graded reflex activation of the renal nerves, compatible with our hypothesis. 4. Thus, sympathetic outflow may be capable of selectively increasing or decreasing glomerular capillary pressure and, hence, GFR by differentially activating separate populations of renal nerves. This has important implications for our understanding of the neural control of body fluid balance in health and disease.
In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2021
DOI: 10.1161/HYPERTENSIONAHA.121.17164
Abstract: Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold P .0001) and MasR (Mas oncoreceptor 2–3-fold, P .05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.
Sustained Decrease in Blood Pressure and Reduced Anatomical and Functional Reinnervation of Renal Nerves in Hypertensive Sheep 30 Months After Catheter-Based Renal Denervation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
DOI: 10.1161/HYPERTENSIONAHA.118.12250
Abstract: We examined whether renal denervation (RDN) reduced blood pressure (BP), improved glomerular filtration rate, albuminuria, and left ventricular mass in sheep with hypertensive chronic kidney disease (CKD). To examine whether renal nerve function returned in the long term, we examined vascular contraction to nerve stimulation in renal arteries and determined nerve regrowth by assessing renal TH (tyrosine hydroxylase), CGRP (calcitonin gene-related peptide), and norepinephrine levels in kidneys at 30 months after RDN. RDN normalized BP in hypertensive CKD sheep such that BP was similar to that of the normotensive sheep with intact nerves. Glomerular filtration rate decreased by ≈22% in CKD sheep with intact nerves but increased ≈26% in hypertensive CKD-RDN sheep by 30 months. At 30 months, urinary albumin was ≈127% and left ventricular mass was ≈41% greater in CKD sheep with intact nerves than control. However, urinary albumin was ≈60% less and left ventricular mass was ≈40% less in the CKD sheep that underwent RDN compared with intact counterpart. At 30 months in CKD-RDN sheep, neurovascular contraction (≈56%), renal proportion of TH (≈50%), CGRP (≈67%), and norepinephrine content (≈49%) were all less than CKD-intact all these variables were similar between normotensive-intact and normotensive-RDN groups. RDN caused a sustained reduction in BP and improvements in renal function. Regrowth of renal nerves and return of function were observed in hypertensive CKD-RDN sheep, but levels were only partially restored to levels of intact. These suggest that RDN lowers BP in the long term and is renoprotective and cardioprotective as a result of lesser nerve regrowth in CKD.
Renal programming: Cause for concern?
Publisher: American Physiological Society
Date: 04-2011
DOI: 10.1152/AJPREGU.00791.2010
Abstract: Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures.
Anti‐fibrotic actions of relaxin
Publisher: Wiley
Date: 07-07-2016
DOI: 10.1111/BPH.13529
Placental Growth Factor
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2016
The anti-fibrotic actions of relaxin are mediated through AT2 R-associated protein phosphatases via RXFP1-AT2 R functional crosstalk in human cardiac myofibroblasts.
Publisher: Wiley
Date: 16-04-2020
Chronic recurrent dehydration associated with periodic water intake exacerbates hypertension and promotes renal damage in male spontaneously hypertensive rats
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
DOI: 10.1038/SREP33855
Abstract: Epidemiological evidence links recurrent dehydration associated with periodic water intake with chronic kidney disease (CKD). However, minimal attention has been paid to the long-term impact of periodic water intake on the progression of CKD and underlying mechanisms involved. Therefore we investigated the chronic effects of recurrent dehydration associated with periodic water restriction on arterial pressure and kidney function and morphology in male spontaneously hypertensive rats (SHR). Arterial pressure increased and glomerular filtration rate decreased in water-restricted SHR. This was observed in association with cyclic changes in urine osmolarity, indicative of recurrent dehydration. Additionally, water-restricted SHR demonstrated greater renal fibrosis and an imbalance in favour of pro-inflammatory cytokine-producing renal T cells compared to their control counterparts. Furthermore, urinary NGAL levels were greater in water-restricted than control SHR. Taken together, our results provide significant evidence that recurrent dehydration associated with chronic periodic drinking hastens the progression of CKD and hypertension, and suggest a potential role for repetitive bouts of acute renal injury driving renal inflammatory processes in this setting. Further studies are required to elucidate the specific pathways that drive the progression of recurrent dehydration-induced kidney disease.
Sympathetic Nervous System and Atherosclerosis
Publisher: MDPI AG
Date: 23-08-2023
Abstract: Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, β1, β2, and β3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of β blockers and β3 agonists are promising therapies against atherosclerosis however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established.
Pressor responsiveness to angiotensin II in female mice is enhanced with age: Role of the angiotensin type 2 receptor
Publisher: Springer Science and Business Media LLC
Date: 16-09-2014
Sex Differences in AT2R Expression and Action
Publisher: Elsevier
Date: 2015
Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction
Publisher: American Physiological Society
Date: 11-2015
DOI: 10.1152/AJPREGU.00403.2014
Abstract: Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was ∼24% lower ( P 0.0001) in LPD offspring this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (∼10 mmHg P 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (∼45%, all P 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.
Chronic maternal hypertension characterized by renal dysfunction is associated with reduced placental blood flow during late gestation in rabbits
Publisher: American Physiological Society
Date: 04-2010
DOI: 10.1152/AJPREGU.00202.2009
Abstract: Maternal hypertension associated with renal disease is a common pregnancy complication. Previously, we have shown in a rabbit model of mild hypertension that offspring from hypertensive mothers have increased blood pressure as adults. In human pregnancy, hypertension has been associated with decreased utero-placental blood flow. The aim of this study was to determine placental blood flow (PBF) in mild (2-kidney-1-wrapped 2K-1W) and moderate (2-kidney-2-wrapped 2K-2W) rabbit models of maternal hypertension. We hypothesized that PBF would be inversely related to the severity of the hypertension. PBF and renal blood flow (RBF) were measured using microspheres on day 28 of a 32-day gestation, in normotensive (sham), 2K-1W, and 2K-2W hypertensive groups. Mean arterial pressure (MAP, ∼7 mmHg, P 0.05) was increased, and RBF (∼35%, P 0.05) was reduced in the 2K-1W and 2K-2W (MAP ∼20 mmHg, P 0.01 RBF ∼53%, P 0.05) groups compared with the sham group. In the 2K-1W group, PBF fell by ∼12% ( P = 0.08) and fetal-to-placental weight ratio increased by ∼12% ( P 0.01) compared with the sham group, reflecting an increase in the functional capacity of the placenta to deliver nutrients to the fetus. In the 2K-2W group, PBF decreased ∼51% ( P 0.05) compared with the sham group, without changes in placental efficiency. Thus, in late gestation, placental blood flow was significantly reduced in the moderate hypertension group, without accompanying changes in fetal or placental weight or placental efficiency. In contrast, mild hypertension resulted in an increase in placental efficiency, without significant changes in placental blood flow. These findings suggest that mild and moderate hypertension may alter placental delivery of nutrients via differing mechanisms dependent upon the severity of the hypertension.
Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
DOI: 10.1161/HYPERTENSIONAHA.111.178715
Abstract: Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II–induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28±6 mm Hg), male AT 2 R-KO (26±2 mm Hg), and female AT 2 R-KO (26±4 mm Hg) mice, however, the response was attenuated in female WT mice (12±4 mm Hg P between sex and genotype=0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice ( P between sex and genotype .05 both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II–dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease.
Sex- and age-related differences in arterial pressure and albuminuria in mice
Publisher: Springer Science and Business Media LLC
Date: 14-11-2016
Effects of early carvedilol treatment and withdrawal on the development of hypertension and renal vascular narrowing
Publisher: Oxford University Press (OUP)
Date: 02-2016
DOI: 10.1016/J.AMJHYPER.2003.09.013
Abstract: The aims of this study were to examine whether combined blockade of alpha(1) and beta-adrenoceptors with carvedilol postweaning affected the development of hypertension and renal vascular narrowing in spontaneously hypertensive rats (SHR), and whether these effects on pressure and renal vascular changes persisted after treatment withdrawal. From 4 to 12 weeks of age male SHR were administered carvedilol in rat chow at 1.2 mg/g chow (low-dose) or 2.4 mg/g chow (high-dose), or were given normal chow. At 12 weeks of age, rats from each group either underwent experimentation or had treatment withdrawn and were studied at 20 weeks. On the experimental day, conscious mean arterial pressure (MAP) was measured and, as a functional test of renal vessel lumen characteristics, pressure-flow and pressure-glomerular filtration rate (pressure-GFR) relationships were determined in the maximally dilated kidney. At 12 weeks of age, SHR on low and high-dose carvedilol had significantly lower MAP than that of untreated SHR (137 +/- 3, 134 +/- 1, 152 +/- 2 mm Hg, respectively P <.001). The SHR treated with high-dose (but not low-dose) carvedilol demonstrated a steeper renal pressure-flow relationship (P <.001), and a leftward shifted (P <.01) and steeper (P <.001) pressure-GFR relationship compared with control SHR. Eight weeks after carvedilol withdrawal, there were no significant differences in MAP, pressure-flow, or pressure-GFR relationships between groups. These results suggest that postweaning alpha(1) and beta-adrenoceptor blockade with high-dose carvedilol attenuated the development of hypertension and led to a preferential reduction in preglomerular resistance (increased lumen dimensions) independent of the effects on MAP. However, treatment of SHR from 4 to 12 weeks of age with high-dose carvedilol did not lead to persistent, long-term effects on arterial pressure or renal vascular narrowing after treatment withdrawal.
Strategies for immortalisation of amnion‐derived mesenchymal and epithelial cells
Publisher: Wiley
Date: 23-08-2022
DOI: 10.1002/CBIN.11892
Abstract: Mesenchymal (human amniotic mesenchymal stem cell [HAMSC]) and epithelial cells (human amnion epithelial cell [HAEC]) derived from human amniotic membranes possess characteristics of pluripotency. However, the pluripotency of HAMSC and HAEC are sustained only for a finite period. This in vitro cell growth can be extended by cell immortalisation. Many well‐defined immortalisation systems have been used for artificially overexpressing genes such as human telomerase reverse transcriptase in HAMSC and HAEC leading to controlled and prolonged cell proliferation. In recent years, much progress has been made in our understanding of the cellular machinery that regulates the cell cycle when immortalised. This review summarises the current understanding of molecular mechanisms that contribute to cell immortalisation, the strategies that have been employed to immortalise amnion‐derived cell types, and their likely applications in regenerative medicine.
Brief early life angiotensin-converting enzyme inhibition attenuates the diuretic response to saline loading in sheep with solitary functioning kidney
Publisher: Portland Press Ltd.
Date: 08-2023
DOI: 10.1042/CS20230663
Abstract: A solitary functioning kidney (SFK) from birth predisposes to hypertension and kidney dysfunction, and this may be associated with impaired fluid and sodium homeostasis. Brief and early angiotensin-converting enzyme inhibition (ACEi) in a sheep model of SFK delays onset of kidney dysfunction. We hypothesized that modulation of the renin–angiotensin system via brief postnatal ACEi in SFK would reprogram renal sodium and water handling. Here, blood pressure (BP), kidney haemodynamics and kidney excretory function were examined in response to an isotonic saline load (0.13 ml/kg/min, 180 min) at 20 months of age in SFK (fetal unilateral nephrectomy at 100 days gestation term 150 days), sham and SFK+ACEi sheep (ACEi in SFK 4–8 weeks of age). Basal BP was higher in SFK than sham (∼13 mmHg), and similar between SFK and SFK+ACEi groups. Saline loading caused a small increase in BP (∼3–4 mmHg) the first 2 h in SFK and sham sheep but not SFK+ACEi sheep. Glomerular filtration rate did not change in response to saline loading. Total sodium excretion was similar between groups. Total urine excretion was similar between SFK and sham animals but was ∼40% less in SFK+ACEi animals compared with SFK animals. In conclusion, the present study indicates that water homeostasis in response to a physiological challenge is attenuated at 20 months of age by brief early life ACEi in SFK. Further studies are required to determine if ACEi in early life in children with SFK could compromise fluid homeostasis later in life.
Impaired ability to modulate glomerular filtration rate in aged female sheep following fetal uninephrectomy
Publisher: Wiley
Date: 2014
DOI: 10.1002/PHY2.208
Long-Term Alteration in Maternal Blood Pressure and Renal Function After Pregnancy in Normal and Growth-Restricted Rats
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
DOI: 10.1161/HYPERTENSIONAHA.112.195578
Abstract: Intrauterine growth restriction is associated with increased risk of adult cardiorenal diseases. Small birth weight females are more likely to experience complications during their own pregnancy, including pregnancy-induced hypertension, preecl sia, and gestational diabetes. We determined whether the physiological demand of pregnancy predisposes growth-restricted females to cardiovascular and renal dysfunction later in life. Late gestation bilateral uterine vessel ligation was performed in Wistar-Kyoto rats. At 4 months, restricted and control female offspring were mated with normal males and delivered naturally (ex-pregnant). Regardless of maternal birth weight, at 13 months, ex-pregnant females developed elevated mean arterial pressure (indwelling tail-artery catheter +6 mm Hg), reduced effective renal blood flow ( 14 C-PAH clearance −23%), and increased renal vascular resistance (+27%) compared with age-matched virgins. Glomerular filtration rate ( 3 H-inulin clearance) was not different across groups. This adverse cardiorenal phenotype in ex-pregnant females was associated with elevated systemic (+57%) and altered intrarenal components of the renin-angiotensin system. After pregnancy at 13 months, coronary flow (Langendorff preparation) was halved in restricted females compared with controls, and together with reduced NO excretion, this may increase susceptibility to additional lifestyle challenges. Our results have implications for aging females who have been pregnant, suggesting long-term cardiovascular and renal alterations, with additional consequences for females who were small at birth.
Renal Denervation Update From the International Sympathetic Nervous System Summit
Publisher: Elsevier BV
Date: 06-2019
VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY
Publisher: Wiley
Date: 12-1990
DOI: 10.1111/J.1440-1681.1990.TB01289.X
Abstract: 1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre- and post-glomerular vascular resistance have been studied in anaesthetized rabbits. 2. Blood pressure did not change significantly in response to 10 ng/kg per min endothelin or vehicle infusion, but rose steadily during infusion of 50 ng/kg per min endothelin, increasing 11.8 +/- 2.7 mmHg by 90 min of infusion. 3. Glomerular filtration fraction (3H-inulin extraction ratio) rose and remained elevated throughout the endothelin infusion at 50 ng/kg per min. GFR did not change significantly until 70-90 min of the infusion (50 ng/kg per min) when it decreased by about 35%. No significant changes were seen at 10 ng/kg per min endothelin. 4. Sodium excretion rate rose in response to the lower dose, due to an increase in fractional sodium excretion. No changes in sodium excretion were seen at the higher dose of endothelin. 5. Glomerular capillary pressure rose significantly in response to endothelin infusion (50 ng/kg per min). 6. Renal blood flow fell progressively in response to endothelin (50 ng/kg per min), to about one-third of the pre-infusion value. 7. Renal vascular resistance increased progressively with both doses of endothelin, by about 35% at 10 ng/kg per min and about 400% at 50 ng/kg per min after 70-90 min. Preglomerular resistance increased from 1.0 +/- 0.1 to 5.0 +/- 1.9 mmHg/mL per min in response to endothelin 50 ng/kg per min. Postglomerular resistance rose from 1.0 +/- 0.1 to 5.6 +/- 2.17 mmHg/mL per min. 8. Thus endothelin infusion caused progressive renal vasoconstriction with similar magnitude increases in both pre- and postglomerular vessels. The vasoconstriction of the kidney caused by endothelin occurred at a dose which did not effect systemic blood pressure.
Control of salt and volume retention cannot be ruled out as a mechanism underlying the blood pressure-lowering effect of renal denervation
Publisher: Springer Science and Business Media LLC
Date: 15-08-2013
DOI: 10.1038/HR.2013.82
Adjustment for body mass index changes inverse associations of HDL-cholesterol with blood pressure and hypertension to positive associations
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41371-021-00548-X
Abstract: The associations between high-density lipoprotein cholesterol (HDL-C) and blood pressure (BP) or hypertension are inconsistent in previous studies. This study aimed to assess these associations in a large cohort of Chinese adults and across different age groups. This cross-sectional association study included 22,081 Chinese adults. Associations of HDL-C with BP and hypertension were analyzed using linear or logistic regression, with or without adjustment for confounding factors. HDL-C was inversely associated with BP and hypertension. These associations were still apparent after adjustment for age, sex, fasting plasma glucose, and low-density lipoprotein cholesterol. Sub-analyses revealed: (1) in the whole cohort and females alone, HDL-C was inversely associated with BP and hypertension in young and middle-aged but not older participants (2) in males alone, HDL-C was not associated with systolic BP or hypertension. However, HDL-C was either inversely, or not, or positively associated with BP in young, middle-aged, and older males, respectively. After further adjustment for body mass index (BMI), the negative associations of HDL-C with BP and hypertension in the whole cohort became positive ones, and the positive associations only presented in males. These findings suggest that further adjustment for BMI changes inverse associations of HDL-cholesterol with BP and hypertension to positive associations in a cohort of Chinese adults.
Nitric oxide in responses of regional kidney perfusion to renal nerve stimulation and renal ischaemia
Publisher: Springer Science and Business Media LLC
Date: 11-2003
DOI: 10.1007/S00424-003-1149-1
Abstract: The mechanisms underlying the relative insensitivity of medullary blood flow (MBF) to sympathetic drive remain unknown. We tested the effects of nitric oxide synthase blockade on regional kidney perfusion responses to electrical renal nerve stimulation (RNS) in pentobarbitone-anaesthetized rabbits. Under control conditions, RNS reduced renal blood flow (RBF), cortical blood flow (CBF) and MBF in a frequency-dependent manner. MBF was always reduced less than CBF or RBF. NG-nitro-L-arginine increased mean arterial pressure (31+/-3 mmHg), reduced RBF (-8+/-1 ml/min) and MBF (-33+/-6 units), enhanced responses to RNS of RBF (from -48+/-6% to -58+/-6% at 2 Hz), CBF (from -38+/-6% to -43+/-4% at 2 Hz) and, particularly at low frequencies, MBF (from +1+/-18% to -32+/-11% at 2 Hz) and potentiated the RBF hyperaemic response following RNS (by 27+/-6% at 4 Hz). When glyceryl trinitrate was co-infused with NG-nitro-L-arginine to restore basal nitrergic tone, responses to RNS and the subsequent hyperaemia were indistinguishable from control. Since resting renovascular tone or perfusion pressure has little impact on MBF responses to RNS, these present observations suggest that NO contributes to the blunted MBF response to RNS. Paradoxically, NO seems to blunt renal hyperaemia following acute RNS-induced ischaemia.
Catheter-Based Renal Denervation Exacerbates Blood Pressure Fall During Hemorrhage
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JACC.2016.12.014
Abstract: Clinical trials applying catheter-based radiofrequency renal denervation (RDN) demonstrated a favorable safety profile with minimal acute or procedural adverse events. Whether ablation of renal nerves adversely affects compensatory responses to hemodynamic challenge has not been extensively investigated. The aim of this study was to examine the effect of RDN on mean arterial pressure, renal function, and the reflex response to hemorrhage in sheep with normotension (control) or with hypertensive chronic kidney disease (CKD). Sheep underwent RDN (control-RDN, n = 8 CKD-RDN, n = 7) or sham procedures (control-intact, n = 6 CKD-intact, n = 7). Response to hemorrhage (20% loss of blood volume), including plasma renin activity, was assessed at 2 and 5 months post-procedure. RDN caused a complete reversal of hypertension and improved renal function in CKD-RDN sheep (p < 0.0001 for 2 and 5 months vs. pre-RDN). In response to hemorrhage, mean arterial pressure fell in all groups, with the fall being greater in the RDN than the intact group (2-month fall in mean arterial pressure: control-intact, -10 ± 1 mm Hg control-RDN, -15 ± 1 mm Hg p < 0.05 CKD-intact, -11 ± 3 mm Hg CKD-RDN, -19 ± 9 mm Hg p < 0.001). Hemorrhage increased heart rate and plasma renin activity in intact sheep, but these responses were significantly attenuated in control-RDN and CKD-RDN animals. Responses to hemorrhage were remarkably similar at 2 and 5 months post-RDN, which suggests that nerve function had not returned within this time frame. In hypertensive CKD sheep, RDN reduced blood pressure and improved basal renal function but markedly compromised compensatory hemodynamic responses to hemorrhage. Therefore, the capacity to respond to a physiological challenge to body fluid homeostasis may be compromised following RDN.
Effect of endothelin-1 on regional kidney blood flow and renal arteriole calibre in rabbits
Publisher: Wiley
Date: 08-2004
Physiological and molecular mechanisms governing sexual dimorphism of kidney, cardiac, and vascular function
Publisher: American Physiological Society
Date: 02-2007
Intricacies of brain angiotensin II signalling pathways
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
Predominant postglomerular vascular resistance response to reflex renal sympathetic nerve activation during ANG II clamp in rabbits
Publisher: American Physiological Society
Date: 10-2004
DOI: 10.1152/AJPREGU.00202.2004
Abstract: We have shown previously that a moderate reflex increase in renal sympathetic nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more severe increase in RSNA decreased glomerular capillary pressure. This suggested that the nerves innervating the glomerular afferent and efferent arterioles could be selectively activated, allowing differential control of glomerular capillary pressure. A caveat to this conclusion was that intrarenal actions of neurally stimulated ANG II might have contributed to the increase in postglomerular resistance. This has now been investigated. Anesthetized rabbits were prepared for renal micropuncture and RSNA recording. One group (ANG II cl ) received an infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg bolus plus 2 mg·kg −1 ·h −1 ) plus ANG II (∼20 ng·kg −1 ·min −1 ), the other vehicle. Measurements were made before (room air) and during 14% O 2 . Renal blood flow decreased less during ANG II cl compared with vehicle [9 ± 1% vs. 20 ± 4%, interaction term (P GT ) 0.05], despite a similar increase in RSNA in response to 14% O 2 in the two groups. Arterial pressure and glomerular filtration rate were unaffected by 14% O 2 in both groups. Glomerular capillary pressure increased from 33 ± 1 to 37 ± 1 mmHg during ANG II cl and from 33 ± 2 to 35 ± 1 mmHg in the vehicle group before and during 14% O 2 , respectively (P GT 0.05). During ANG II cl , postglomerular vascular resistance was still increased in response to RSNA during 14% O 2 , demonstrating that the action of the renal nerves on the postglomerular vasculature was independent of the renin-angiotensin system. This further supports our hypothesis that increases in RSNA can selectively control pre- and postglomerular vascular resistance and therefore glomerular ultrafiltration.
Effects of activation of vasopressin-V1-receptors on regional kidney blood flow and glomerular arteriole diameters
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2001
DOI: 10.1097/00004872-200103001-00019
Abstract: We tested whether vasoconstriction of juxtamedullary glomerular arterioles contributes to vasopressin V1 -receptor-mediated reductions in medullary perfusion (MBF). The left kidney of pentobarbitone anaesthetized rabbits was denervated, a perivascular flow probe placed around the renal artery and laser-Doppler flow probes positioned in the inner medulla and on the cortical surface. Rabbits then received a 30 min intravenous infusion of [Phe2,Ile3,Orn8]vasopressin (V1 -AG 30 ng/kg per min n = 7) or its vehicle (n = 7). Kidneys were perfusion fixed at the final recorded mean arterial pressure (MAP) and filled with methacrylate casting material. Diameters of afferent and efferent arterioles were determined by scanning electron microscopy. V1 -AG increased MAP (19 +/- 3%) and reduced MBF (30 +/- 8%) but not cortical perfusion or total renal blood flow. Vehicle-treatment did not significantly affect these variables. After vehicle- and V1-AG-treatment, juxtamedullary afferent arteriole luminal diameter averaged 15.35 +/- 1.31 and 15.88 +/- 1.86 microm, respectively (P= 0.92), while juxtamedullary efferent arteriole luminal diameter averaged 17.75 +/- 1.86 and 18.36 +/- 2.24 microm, respectively (P= 0.93). V1-AG reduced MBF but did not significantly affect juxtamedullary arteriolar diameter. Our results therefore do not support a role for juxtamedullary arterioles in producing V1-receptor-mediated reductions in MBF, suggesting that downstream vascular elements (e.g. outer medullary descending vasa recta) might be involved.
Renovascular hypertension: Structural changes in the renal vasculature
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2000
Abstract: Abstract —Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.
Programming Hypertension—Animal Models
Publisher: Springer US
Date: 2006
Effects of tempol and candesartan on neural control of the kidney
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.AUTNEU.2012.01.007
Abstract: We compared the effects of tempol (300 μmol kg(-1) plus 300 μmol kg(-1) h(-1), n=14) and candesartan (10 μg kg(-1) plus 10 μg kg(-1) h(-1), n=14) on renal haemodynamics, excretory function, and responses to electrical stimulation of the renal nerves (RNS) in lean and obese rabbits under pentobarbitone anaesthesia. Depressor responses to tempol (-16 ± 2 mmHg) and candesartan (-12 ± 1 mmHg) were similar. Candesartan, but not tempol, significantly increased basal renal blood flow (RBF +36 ± 7%). Tempol, but not candesartan, significantly reduced glomerular filtration rate (GFR -30 ± 10%) and sodium excretion (U(Na)V -44 ± 14%). RNS induced frequency-dependent reductions in RBF (-20 ± 3% at 1 Hz), GFR (-28 ± 6% at 1 Hz) and U(Na)V (-55 ± 6% at 1 Hz). Candesartan blunted these responses. Tempol did not significantly alter RBF and GFR responses to RNS but blunted the U(Na)V response. Responses to RNS, and the effects of tempol and candesartan, were similar in lean compared with obese rabbits. Unlike candesartan, tempol did not induce renal vasodilatation, maintain GFR and U(Na)V during reductions in arterial pressure, or blunt neurally-mediated vasoconstriction. In conclusion, unlike the AT(1)-receptor antagonist candesartan, tempol does not blunt the effects of RNS on renal haemodynamic function. Furthermore, under the current experimental conditions superoxide appears to make little contribution to the actions of endogenous angiotensin II on baseline renal haemodynamics or excretory function, or their responses to RNS.
Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPRENAL.00139.2011
Abstract: Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386–396, 2009 Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669–680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 ± 7% P group × treatment 0.001), due to a paradoxical decrease in renal vascular resistance ( P group × treatment 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 ± 35 vs. 25 ± 12% P 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated.
Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy
Publisher: American Physiological Society
Date: 04-2012
DOI: 10.1152/AJPREGU.00579.2011
Abstract: We have previously shown that fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days) in male sheep results in a 30% nephron deficit, reduction in glomerular filtration rate (GFR) and renal blood flow, and elevation in arterial pressure at 6 mo of age. Furthermore, in response to an acute 0.9% saline load, sodium excretion was significantly delayed in uni-x animals leading us to speculate that tubuloglomerular feedback (TGF) activity was reset in uni-x animals. In the present study, we induced TGF blockade by furosemide administration (1.5 mg/kg iv over 90 min) and determined GFR, effective renal plasma flow, and urine and sodium excretion responses in 6-mo-old male sheep. In response to furosemide, a significant diuresis and natriuresis was observed in the sham group however, the response was significantly delayed and reduced in uni-x animals (both, P treatment×time 0.001). Cummulative urinary and sodium output was significantly less in the uni-x compared with the sham sheep (both, P treatment×time 0.001). GFR was increased in the sham but not the uni-x sheep ( P treatment×time 0.0001). In conclusion, the excretory response to furosemide was attenuated in the uni-x sheep, and this suggests a rightward resetting of the TGF operating point. The TGF mechanism is important in the fine tuning of sodium homeostasis and is likely a contributing factor for the dysfunction in sodium regulation we have previously observed in the uni-x animals.
Review: Sex specific programming: A critical role for the renal renin-angiotensin system
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.PLACENTA.2010.01.006
Abstract: The "Developmental Origins of Health and Disease" hypothesis has caused resurgence of interest in understanding the factors regulating fetal development. A multitude of prenatal perturbations may contribute to the onset of diseases in adulthood including cardiovascular and renal diseases. Using animal models such as maternal glucocorticoid exposure, maternal calorie or protein restriction and uteroplacental insufficiency, studies have identified alterations in kidney development as being a common feature. The formation of a low nephron endowment may result in impaired renal function and in turn may contribute to disease. An interesting feature in many animal models of developmental programming is the disparity between males and females in the timing of onset and severity of disease outcomes. The same prenatal insult does not always affect males and females in the same way or to the same degree. Recently, our studies have focused on changes induced in the kidney of both the fetus and the offspring, following a perturbation during pregnancy. We have shown that changes in the renin-angiotensin system (RAS) occur in the kidney. The changes are often sex specific which may in part explain the observed sex differences in disease outcomes and severity. This review explores the evidence suggesting a critical role for the RAS in sex specific developmental programming of disease with particular reference to the immediate and long term changes in the local RAS within the kidney.
The his and hers of the renin-angiotensin system
Publisher: Springer Science and Business Media LLC
Date: 21-11-2013
DOI: 10.1007/S11906-012-0319-Y
Abstract: Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT(1)R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT(2)R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.
Fetal growth and well‐being in a study of maternal hypertension in rabbits
Publisher: Wiley
Date: 08-01-2020
DOI: 10.1002/AR.24344
Abstract: Obtaining growth and physiologic data in the postnatal laboratory animal is common. However, monitoring growth in utero is far more difficult, with little data available except upon termination of pregnancy. High-resolution ultrasound was used to monitor growth, morphology, and fetal well-being in normotensive and hypertensive rabbits (21 fetuses) at day 16, 20, and 26 of the 32 day gestational period. Set protocols, comparable to those routinely assessed in humans, were devised and followed for each examination. Birth weight was greater in offspring of hypertensive as compared to normotensive mothers (p < 0.001) however, litter size was reduced. The greater birth weight was reflected in growth parameters measured throughout gestation indicating the predictive value of ultrasound. High-resolution ultrasound was a reliable and sensitive method for biometric and morphologic assessment of the fetal rabbit, demonstrating that growth trajectory of offspring of hypertensive mothers may be altered early in gestation.
Type 1 neuropeptide Y receptors and α1-adrenoceptors in the neural control of regional renal perfusion
Publisher: American Physiological Society
Date: 02-2006
DOI: 10.1152/AJPREGU.00317.2005
Abstract: The aim of this study was to determine the contribution of neuropeptide Y (NPY) Y 1 receptors in neurally mediated reductions in renal medullary perfusion. In pentobarbital sodium-anesthetized rabbits, electrical stimulation of the renal nerves (RNS, 0.5–16 Hz) decreased renal perfusion in a frequency-dependent manner. Under control conditions, 4 Hz reduced cortical and medullary perfusion by −85 ± 3% and −43 ± 7%, whereas 8 Hz reduced them by −93 ± 2% and −73 ± 4%, respectively. After Y 1 receptor antagonism with BIBO3304TF (0.1 mg/kg plus 0.2 mg·kg· −1 ·h −1 ), RNS reduced perfusion less (by −65 ± 9% and −12 ± 8% at 4 Hz). α 1 -Adrenoceptor antagonism with prazosin (0.2 mg/kg plus 0.2 mg kg −1 h −1 ) also inhibited RNS-induced reductions in renal perfusion (−80 ± 4% and −37 ± 10% reductions in the cortex and medulla, respectively, at 8 Hz). When given after BIBO3304TF treatment, prazosin inhibited RNS-induced reductions in cortical and medullary perfusion more profoundly (−57 ± 12% and −25 ± 9% reductions, respectively, at 8 Hz). Y 1 receptor- and α 1 -adrenoceptor-blockade were confirmed by testing vascular responses to renal arterial NPY and phenylephrine boluses. NPY-positive immunolabeling was observed around interlobular arteries, afferent and efferent arterioles, and in the outer medulla. In conclusion, Y 1 receptors and α 1 -adrenoceptors contribute to RNS-induced vasoconstriction in the vessels that control both cortical and medullary perfusion. Consistent with this, NPY immunostaining was associated with blood vessels that control perfusion in both regions. There also seems to be an interaction between Y 1 receptors and α 1 -adrenoceptor-mediated neurotransmission in the control of renal perfusion.
DECREASED RENAL RESPONSES TO ATRIAL NATRIURETIC PEPTIDE IN RENAL WRAP HYPERTENSION
Publisher: Wiley
Date: 04-1988
DOI: 10.1111/J.1440-1681.1988.TB01071.X
Abstract: 1. The effects of atrial natriuretic polypeptide (ANP) on renal function were examined in renal wrap hypertensive rabbits and sham operated rabbits. 2. ANP (2 micrograms/min) induced hypotension, but did not produce significant diuresis, natriuresis or change in the glomerular filtration rate (GFR) in renal wrap hypertensive rabbits (n = 8). 3. In sham operated normotensive rabbits (n = 4), ANP induced significant diuresis (230%) and increased GFR by about 40%. 4. Thus, ANP was markedly less effective in the impaired kidneys of renal wrapped rabbits than in normal kidneys.
Sex differences in the renal vascular response to angiotensin II involves the M as receptor
Publisher: Wiley
Date: 11-08-2012
DOI: 10.1111/J.1748-1716.2012.02468.X
Abstract: The renin-angiotensin system (RAS) depressor arm, particularly renal angiotensin type 2 receptor (AT(2) R) and Mas receptor (masR) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that masR activation increases renal blood flow (RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (AngII) infusion in female rats. Furthermore, we postulated that combined activation of the AT(2) R and masR would produce a greater response than masR activation alone. In anaesthetized male and female Wistar rats, mean arterial pressure (MAP) and RBF responses during graded AngII infusion (30-1000 ng kg(-1) min(-1) i.v.) were assessed following pre-treatment with vehicle, the masR antagonist A779, or A779 plus the AT(2) R antagonist PD123319. Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female (P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. AngII infusion reduced RBF in a dose-related fashion (P(dose) < 0.0001) and masR blockade did not alter the RBF response to AngII infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to AngII in females (P(group) < 0.005), but not males. The impact of the masR on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT(2) R and masR blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT(2) R and/or masR stimulation can be advanced.
Prenatal Exposure to Alcohol Reduces Nephron Number and Raises Blood Pressure in Progeny
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2010
Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2005
DOI: 10.1097/01.HJH.0000163155.29740.D2
Abstract: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.
Perinatal Programming of Arterial Pressure
Publisher: Springer International Publishing
Date: 2017
Sex-related differences in hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
Increase in Bioavailability of Nitric Oxide After Renal Denervation Improves Kidney Function in Sheep With Hypertensive Kidney Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/HYPERTENSIONAHA.120.16718
Abstract: Overactivity of renal sympathetic nerves and nitric oxide (NO) deficiency occur in hypertensive chronic kidney disease (CKD). In sheep with hypertensive CKD and NO deficiency, renal denervation (RDN) reduces blood pressure and improves kidney function (glomerular filtration rate). We hypothesized that this improvement in glomerular filtration rate after RDN is associated with increased NO bioavailability. In this study, glomerular filtration rate response to systemic inhibition of NOS (NO synthase) was examined in healthy and CKD sheep at 2 and 30 months after a sham (intact nerves) or RDN procedure. Basal urinary total nitrate (nitrate+nitrite) excretion was examined at 2 and 30 months, and kidney protein expression of endothelial and neuronal NOS was assessed at 30 months. Urinary nitrate+nitrite in CKD-RDN and healthy sheep was ≈50% to 70% greater than in CKD-intact. During NOS inhibition, the fall in glomerular filtration rate in CKD-RDN sheep was ≈20% greater than in CKD-intact. These effects in CKD-RDN sheep were similar to those in healthy sheep. Endothelial NOS protein expression was lower in CKD-intact sheep compared with healthy sheep and compared with CKD-RDN. In summary, RDN normalizes NO bioavailability and restores contribution of NO to renal hemodynamics in CKD. These changes may promote improvements in kidney function and sustained blood pressure lowering after RDN in hypertensive CKD.
Neural control of renal medullary perfusion
Publisher: Wiley
Date: 05-2004
DOI: 10.1111/J.1440-1681.2004.04003.X
Abstract: 1. There is strong evidence that the renal medullary circulation plays a key role in long‐term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). 2. The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. 3. Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. 4. Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. 5. Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter‐regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II‐induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. 6. Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension.
Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice
Publisher: Springer Science and Business Media LLC
Date: 16-03-2016
DOI: 10.1007/S00109-016-1406-3
Abstract: This study investigated the effect of post-stroke, direct AT2-receptor (AT2R) stimulation with the non-peptide AT2R-agonist compound 21 (C21) on infarct size, survival and neurological outcome after middle cerebral artery occlusion (MCAO) in mice and looked for potential underlying mechanisms. C57/BL6J or AT2R-knockout mice (AT2-KO) underwent MCAO for 30 min followed by reperfusion. Starting 45 min after MCAO, mice were treated once daily for 4 days with either vehicle or C21 (0.03 mg/kg ip). Neurological deficits were scored daily. Infarct volumes were measured 96 h post-stroke by MRI. C21 significantly improved survival after MCAO when compared to vehicle-treated mice. C21 treatment had no impact on infarct size, but significantly attenuated neurological deficits. Expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) (receptor for BDNF) and growth-associated protein 43 (GAP-43) were significantly increased in the peri-infarct cortex of C21-treated mice when compared to vehicle-treated mice. Furthermore, the number of apoptotic neurons was significantly decreased in the peri-infarct cortex in mice treated with C21 compared to controls. There were no effects of C21 on neurological outcome, infarct size and expression of BDNF or GAP-43 in AT2-KO mice. From these data, it can be concluded that AT2R stimulation attenuates early mortality and neurological deficits after experimental stroke through neuroprotective mechanisms in an AT2R-specific way. Key message • AT2R stimulation after MCAO in mice reduces mortality and neurological deficits.• AT2R stimulation increases BDNF synthesis and protects neurons from apoptosis.• The AT2R-agonist C21 acts protectively when applied post-stroke and peripherally.
Transcutaneous assessment of glomerular filtration rate in unanesthetized rats using a small animal imager: impact on arterial pressure, heart rate, and activity
Publisher: Wiley
Date: 10-2016
DOI: 10.14814/PHY2.12723
Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-01-2015
DOI: 10.1161/CIRCULATIONAHA.114.013930
Abstract: Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep. In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition ( N ω -nitro- l -arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower ( P .001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep ( P Interaction .01). Endothelial NO synthase and Ser-1177–phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep ( P .05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression ( P .05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep ( P .05). Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products
Publisher: Springer Science and Business Media LLC
Date: 23-02-2006
DOI: 10.1007/S00125-006-0175-X
Abstract: The aim of this study was to investigate the effects of a secondary renal insult, due to chronic infusion of AGEs on renal function, and on early pathological markers in rats with a developmental nephron deficit. Female Wistar-Kyoto rats were fed a low-protein diet (LPD 8.7% casein) or a normal-protein diet (NPD 20% casein) during pregnancy and lactation. Nephron number was estimated in 4-week-old female offspring. Male offspring were allowed to grow to 20 weeks of age, when AGEs derived from BSA (AGE-BSA) or BSA was infused subcutaneously (20 mg kg(-1) day(-1)) for 4 weeks. At 24 weeks, blood pressure, renal function and circulating and renal AGEs were assessed. Real-time PCR was used to investigate early molecular markers of renal pathology. As expected, maternal protein restriction led to reduced nephron endowment in LPD offspring. This alone did not affect blood pressure or lead to hyperfiltration in adulthood. However, when coupled with the secondary renal insult, the expression of the genes encoding transforming growth factor-beta(1) and procollagen III was significantly upregulated in the kidneys. In addition, there was renal accumulation of AGEs in LPD offspring, and this was exacerbated by AGE infusion. Our results demonstrate that the adult kidney with a reduced nephron endowment is more vulnerable to secondary renal insult from AGE-BSA. Since AGE formation is markedly elevated with hyperglycaemia, our findings suggest that a developmental or acquired deficit may render the kidney susceptible to diabetic renal disease.
Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
DOI: 10.1161/HYPERTENSIONAHA.113.02809
Abstract: Accumulating evidence suggests that the protective pathways of the renin–angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100–300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats ( P Treatment .001), without influencing arterial pressure. For ex le, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline P .05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT 2 R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT 2 R expression in female than in male hypertensive rats. Taken together, acute AT 2 R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT 2 R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT 2 R as a therapeutic target for cardiovascular disease, particularly in women.
Sex differences in pressure diuresis/natriuresis in rabbits
Publisher: Wiley
Date: 08-2000
DOI: 10.1046/J.1365-201X.2000.00749.X
Abstract: We tested for sex-related differences in the pressure diuresis/natriuresis relationships in anaesthetized, renally denervated rabbits, using an extracorporeal circuit to perfuse the left kidney with the rabbit's own blood, through a series of step-wise increases in renal artery pressure (RAP) (from 65 to 130 mmHg). Urine flow, sodium excretion, and the fractional excretions of sodium and urine increased with increasing RAP, and were greater in male than in female rabbits at all levels of RAP-tested. However, these apparent sex-related differences in the acute pressure diuresis/natriuresis relationships were not reflected in alterations in chronic regulation of mean arterial pressure (MAP). Thus, in rabbits on a normal salt diet (0.85 g day(-1)), resting conscious MAP was significantly greater in males (87 +/- 3 mmHg) compared with females (77+/-1 mmHg). Chronically increasing daily salt intake to 4.98 g day(-1) for 28 days had no significant effect on resting conscious MAP in either sex. Thus, although our observations indicate sex differences, at least under the present experimental conditions, in the factors regulating extracellular fluid volume, these do not appear to have a major impact in setting the level of MAP in the long term.
Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2009
Angiotensin Type 2 Receptor: Hidden Partner
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Erratum
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/PR.2015.17
Glomerular hypertension and hyperfiltration in adrenocorticotrophin-induced hypertension in rats: The role of nitric oxide
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2001
DOI: 10.1097/00004872-200102000-00021
Abstract: To determine the effects on pre- and post-glomerular vascular resistance of adrenocorticotrophin (ACTH)-induced hypertension in rats, before and after blockade of nitric oxide formation. Four groups of Sprague-Dawley rats were studied. Measurements were made in ACTH- (Synacthen Depot, 0.25 mg/kg twice daily for 8 days) and sham-treated anaesthetized rats, before and after either Nomega-nitro-L-arginine (L-NNA, 6 mg/kg) or vehicle. Whole-kidney and single-nephron haemodynamics and function were measured. Glomerular capillary pressure was estimated from tubular stop-flow pressure measurements. Blood pressure (P < 0.001), renal blood flow (RBF, P < 0.05) and glomerular filtration rate (P < 0.01) were increased following ACTH treatment compared with sham. There were no differences in either total renal, or pre- or post-glomerular vascular resistances, but stop-flow-estimated glomerular capillary pressure was elevated (P < 0.001) as was single-nephron glomerular filtration rate (SNGFR) (P < 0.001) and single-nephron blood flow (P < 0.01 ) in the ACTH- compared to the sham-treated rats. L-NNA treatment increased blood pressure by a similar extent in both ACTH- and sham-treated rats, but reduced RBF (P < 0.05) and glomerular filtration rate (GFR) (P < 0.05) more in the ACTH group similar changes were seen in single-nephron values. L-NNA increased pre- and post-glomerular resistances to a greater extent in the ACTH group. ACTH-induced hypertension produced glomerular hypertension and hyperfiltration, which may be due to nitric oxide-related vasodilatation of the renal vasculature.
Beneficial effects of brief early life angiotensin-converting enzyme inhibition wane with time in sheep with solitary functioning kidney
Publisher: Portland Press Ltd.
Date: 04-2023
DOI: 10.1042/CS20220811
Abstract: A child with a congenital solitary functioning kidney (SFK) may develop kidney disease from early in life due to hyperfiltration injury. Previously, we showed in a sheep model of SFK that brief angiotensin-converting enzyme inhibition (ACEi) early in life is reno-protective and increases renal functional reserve (RFR) at 8 months of age. Here we investigated the long-term effects of brief early ACEi in SFK sheep out to 20 months of age. At 100 days gestation (term = 150 days) SFK was induced by fetal unilateral nephrectomy, or sham surgery was performed (controls). SFK lambs received enalapril (SFK+ACEi 0.5 mg/kg, once daily, orally) or vehicle (SFK) from 4 to 8 weeks of age. At 8, 14 and 20 months of age urinary albumin excretion was measured. At 20 months of age, we examined basal kidney function and RFR via infusion of combined amino acid and dopamine (AA+D). SFK+ACEi resulted in lower albuminuria (∼40%) at 8 months, but not at 14 or 20 months of age compared with vehicle-SFK. At 20 months, basal GFR (∼13%) was lower in SFK+ACEi compared with SFK, but renal blood flow (RBF), renal vascular resistance (RVR) and filtration fraction were similar to SFK. During AA+D, the increase in GFR was similar in SFK+ACEi and SFK animals, but the increase in RBF was greater (∼46%) in SFK+ACEi than SFK animals. Brief ACEi in SFK delayed kidney disease in the short-term but these effects were not sustained long-term.
Effect of renal denervation on the development of cellophane-wrap hypertension in rabbits
Publisher: Informa UK Limited
Date: 1986
DOI: 10.3109/10641968609044090
Abstract: The development of hypertension in rabbits with bilateral cellophane wrapping of the kidneys was studied in animals with and without surgical denervation of the kidneys. Mean arterial pressure was measured before and 14 and 28 days after surgery. After 14 and 28 days of wrapping, mean arterial pressure had increased 12 +/- 3 mmHg and 31 +/- 3 mmHg in rabbits with innervated kidneys and 7 +/- 2 mmHg and 26 +/- 2 mmHg in rabbits with denervated kidneys, respectively. The increases in arterial pressure were significantly less in the denervated animals. In sham wrap animals, renal denervation also resulted in significantly lower arterial pressure than in sham wrap+sham denervated rabbits. Noradrenaline concentration of denervated kidneys averaged only 4% of that measured in kidneys subjected to sham denervation. The results show that renal denervation slightly attenuated the degree of hypertension developed following renal wrapping. Since renal denervation produced a similar small decrease in arterial pressure in normotensive rabbits it is suggested that the effect is non-specific and probably due to loss of efferent renal sympathetic nerves.
Mechanisms underlying the diffential control of blood flow in the renal medulla and cortex
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
DOI: 10.1097/01.HJH.0000133744.85490.9D
Abstract: There is much evidence that the medullary circulation plays a key role in regulating renal salt and water handling and, accordingly, the long-term level of arterial pressure. It has also recently become clear that various regulatory factors can affect medullary blood flow (MBF) differently from cortical blood flow (CBF). It appears likely that the influence of hormonal and neural factors on the control of arterial pressure is mediated partly through their impact on MBF. In this review, we focus on the mechanisms underlying the differential control of MBF and CBF, particularly the relative insensitivity of MBF to vasoconstrictors such as angiotensin II, endothelin-1 and the sympathetic nerves. The vascular architecture of the kidney appears to be arranged in a way that protects the renal medulla from ischaemic insults, with juxtamedullary arterioles, the source of MBF, having larger calibre than their counterparts in other kidney regions. Indeed, recent studies using vascular casting methodology suggest that juxtamedullary glomerular arterioles are not the chief regulators of MBF, which is consistent with the idea that outer medullary descending vasa recta play a key role in MBF control. Release of vasoactive paracrine factors such as nitric oxide and various eicosanoids from the vascular endothelium, and probably also from the tubular epithelium, appear to differentially modulate responses of MBF and CBF to hormonal and neural factors. The prevailing intrarenal hormonal milieu and existing haemodynamic conditions also appear to strongly modulate these responses, indicating that multiple control systems interact to regulate regional kidney blood flow at an integrative level.
Adenosine receptors: A tantalizing target for the treatment of salt-sensitive hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
Moxonidine Increases Uptake of Oxidised Low-Density Lipoprotein in Cultured Vascular Smooth Muscle Cells and Inhibits Atherosclerosis in Apolipoprotein E-Deficient Mice
Publisher: MDPI AG
Date: 14-02-2023
DOI: 10.3390/IJMS24043857
Abstract: This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE−/− mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE−/− mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma.
Blunted Sodium Excretion in Response to a Saline Load in 5 Year Old Female Sheep Following Fetal Uninephrectomy
Publisher: Public Library of Science (PLoS)
Date: 15-10-2012
GPCRs (G-Protein-Coupled Receptors) as Microprocessors: Focus on the AT1R (Angiotensin II Type 1 Receptor).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2021
Sex-and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor
Publisher: American Physiological Society
Date: 15-10-2014
DOI: 10.1152/AJPRENAL.00288.2014
Abstract: Sex hormones regulate the renin-angiotensin system. For ex le, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.
Diversity of responses of renal cortical and medullary blood flow to vasoconstrictors in conscious rabbits
Publisher: Wiley
Date: 08-2000
DOI: 10.1046/J.1365-201X.2000.00741.X
Abstract: The medullary microcirculation receives only about 10% of total renal blood flow, but plays a critical role in long-term arterial pressure regulation, so we need to better understand its regulation. Although there is evidence that circulating and locally acting hormones can differentially affect cortical and medullary blood flow in anaesthetized animals, there is little information from studies in conscious animals. This study is aimed (i) to develop a method for chronic measurement of cortical and medullary blood flow in conscious rabbits, and (ii) to test whether renal cortical and medullary blood flow can be differentially affected by intravenous (i.v.) infusions of various vasoconstrictor hormones in conscious rabbits. At preliminary operations, rabbits were equipped with single-fibre laser-Doppler flowprobes in the (left) renal cortex and medulla, and Transonic flowprobes for measuring cardiac output and renal blood flow. Intravenous angiotensin II (300 ng kg(-1) min(-1)), [Phe2,Ile3,Orn8]-vasopressin (30 ng kg(-1) min(-1)), noradrenaline (300 ng kg(-1) min(-1)), endothelin-1 (20 ng kg(-1) min(-1)) and N G-nitro-L-arginine (10 mg kg(-1)) increased mean arterial pressure (by 10-45% of baseline) and reduced heart rate (by 16-35%) and cardiac output (by 16-45%). Consistent with previous observations in anaesthetized rabbits, all treatments except [Phe2,Ile3, Orn8]-vasopressin reduced renal blood flow (13-63%) and cortical blood flow (16-47%), but medullary blood flow was significantly reduced only by [Phe2,Ile3,Orn8]-vasopressin (41%) and N G-nitro-L-arginine (42%). The ersity of these responses of cortical and medullary blood flow to i.v. infusions of vasoconstrictors provides further evidence for physiological roles of circulating and local hormones in the differential regulation of regional kidney blood flow.
Sex differences in the role of the angiotensin type 2 receptor in the regulation of blood pressure
Publisher: Elsevier
Date: 2019
AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-09-2019
Abstract: Studies have shown that the hormone serelaxin, which has organ-protective actions mediated via relaxin family peptide receptor 1 (RXFP1), its cognate G protein–coupled receptor, requires the angiotensin II type 2 receptor (AT 2 R) to ameliorate renal fibrogenesis in vitro and in vivo . In this study, the authors describe a functional interaction between RXFP1, AT 2 R, and the angiotensin II type 1 receptor (AT 1 R), all of which are expressed on extracellular matrix–producing myofibroblasts, the cellular basis of progressive fibrosis. The crosstalk between these G protein–coupled receptors allows antagonists acting at each receptor to directly or allosterically block the antifibrotic actions of agonists acting at AT 2 R or RXFP1. These findings have significant therapeutic implications for a mechanistic understanding of the concomitant use of drugs acting at each receptor. Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT 2 R) to ameliorate renal fibrogenesis in vitro and in vivo . Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT 1 R), which is expressed on myofibroblasts along with RXFP1 and AT 2 R, is unknown. We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro , and in three models of renal- or cardiomyopathy-induced fibrosis in vivo . The AT 1 R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo . Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system that serelaxin did not directly bind to AT 1 Rs but that constitutive AT 1 R–RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an AT 2 R agonist (compound 21). These findings have significant implications for the concomitant use of RXFP1 or AT 2 R agonists with AT 1 R blockers, and suggest that functional interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.
Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.GENM.2011.12.003
Abstract: Sex differences in the expression of the angiotensin (Ang) II receptors and angiotensin-converting enzyme 2 (ACE2) have been hypothesized to be a potential mechanism contributing to sex-specific differences in arterial pressure. Currently, sex differences in the expression of the angiotensin receptors and ACE2 remain undefined. The aim of this study was to define the postnatal ontogeny of mRNA expression, from birth to adulthood, of the Ang II and Ang-(1-7) receptors and ACE2 in male and female rats. Kidney and heart tissue was collected from male and female Sprague Dawley rats and snap-frozen at postnatal days (PNDs) 1, 30, 42, 70, and 110 (adult), and real-time polymerase chain reaction was performed to determine relative expression of the Ang II and Ang-(1-7) receptors (AT(1a)R, AT(1b)R, AT(2)R, and MasR) and ACE2. All these components of the renin-angiotensin system (RAS) were detected in the kidney and left ventricle, although expression levels differed significantly between the sexes and across organs. Gene expression of most components of the RAS was high at birth and decreased with age in both sexes, except for ACE2 expression, which increased in the left ventricle with age (P(Age) < 0.001). Low levels of AT(2)R were observed in the ventricles in both sexes as adults. Most notably, AT(2)R expression was greatest in female kidneys and lowest in male kidneys compared with the left ventricle (P(Age*Sex) < 0.05). Interestingly, MasR expression in the female kidney was similar to the level of AT(2)R expression. Left ventricular MasR expression was greater than AT(2)R expression in both sexes but was not different between the sexes. The highest level of ACE2 expression was observed in adult female kidneys (P(AS) < 0.05). The enhanced mRNA expression of the vasodilatory arm of the renal RAS (ACE2, AT(2)R) in females observed in the present study may contribute to sex differences in the regulation of arterial pressure and the incidence of cardiovascular disease in women.
Developmental programming of a reduced nephron endowment: More than just a baby's birth weight
Publisher: American Physiological Society
Date: 2009
DOI: 10.1152/AJPRENAL.00049.2008
Abstract: The risk of developing many adult-onset diseases, including hypertension, type 2 diabetes, and renal disease, is increased in low-birth-weight in iduals. A potential underlying mechanism contributing to the onset of these diseases is the formation of a low nephron endowment during development. Evidence from the human, as well as many experimental animal models, has shown a strong association between low birth weight and a reduced nephron endowment. However, other animal models, particularly those in which the mother is exposed to elevated glucocorticoids for a short period, have shown a 20–40% reduction in nephron endowment without discernible changes in the birth weight of offspring. Such findings emphasize that a low birth weight is one, but certainly not the only, predictor of nephron endowment and suggests reduced nephron endowment and risk of developing adult-onset disease, even among normal-birth-weight in iduals. Recognition of the dissociation between birth weight and nephron endowment is important for future studies aimed at elucidating the role of a reduced nephron endowment in the developmental programming of adult disease.
Evidence for a renomedullary vasodepressor system in rabbits and dogs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1991
Abstract: Renal perfusion was increased in anesthetized rabbits and dogs by using an extracorporeal circuit. When left kidney perfusion pressure was raised in rabbits (145-240 mm Hg), arterial pressure fell by 1.34 +/- 0.20 mm Hg/min. Pretreatment of the rabbits with 2-bromoethylamine hydrobromide, which destroyed the renal medulla, abolished the fall in arterial pressure (-0.08 +/- 0.08 mm Hg/min) in response to increased renal perfusion pressure. In dogs (with blockade of autonomic ganglia by pentolinium, converting enzyme inhibition [captopril/enalaprilat], and surgical renal denervation), increasing renal perfusion pressure to 170-220 mm Hg resulted in a fall in arterial pressure by 0.32 +/- 0.03 mm Hg/min (or by 28.9 +/- 3.1 mm Hg over a 90-minute period). Mean arterial pressure did not change significantly in identically prepared dogs not subjected to increased renal perfusion pressure, whereas pretreatment of dogs with bromoethylamine abolished the hypotensive response to increased renal perfusion pressure. Thus, the hypotensive response to increased renal perfusion was dependent on the presence of an intact renal medulla, but hypotension still occurred in the presence of converting enzyme inhibition, autonomic ganglion blockade, and renal denervation. The results provide in vivo evidence in two species that a vasodepressor factor from the renal medulla is released in response to increased renal perfusion.
AT<inf>2</inf>R, Vascular Effects, and Blood Pressure
Publisher: Elsevier
Date: 2015
Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation
Publisher: Springer Science and Business Media LLC
Date: 03-08-2004
DOI: 10.1007/S00424-004-1320-3
Abstract: We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N(G)-nitro-L: -arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF -82+/-3% at 6 Hz), cortical laser-Doppler flux (CLDF -84+/-4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF -46+/-7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies < or = 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.
Reduced nephron endowment due to fetal uninephrectomy impairs renal sodium handling in male sheep
Publisher: Portland Press Ltd.
Date: 09-03-2010
DOI: 10.1042/CS20090479
Abstract: Reduced nephron endowment is associated with development of renal and cardiovascular disease. We hypothesized this may be attributable to impaired sodium homoeostasis by the remaining nephrons. The present study investigated whether a nephron deficit, induced by fetal uninephrectomy at 100 days gestation (term=150 days), resulted in (i) altered renal sodium handling both under basal conditions and in response to an acute 0.9% saline load (50 ml·kg−1 of body weight·30 min−1) (ii) hypertension and (iii) altered expression of renal channels/transporters in male sheep at 6 months of age. Uninephrectomized animals had significantly elevated arterial pressure (90.1±1.6 compared with 77.8±2.9 mmHg P& .001), while glomerular filtration rate and renal blood flow (per g of kidney weight) were 30% lower than that of the sham animals. Total kidney weight was similar between the groups. Renal gene expression of apical NHE3 (type 3 Na+/H+ exchanger), ENaC (epithelium Na+ channel) β and γ subunits and basolateral Na+/K+ ATPase β and γ subunits were significantly elevated in uninephrectomized animals, while ENaC α subunit expression was reduced. Urine flow rate and sodium excretion increased in both groups in response to salt loading, but this increase in sodium excretion was delayed by approximately 90 min in the uninephrectomized animals, while total sodium output was 12% in excess of the infused load (P& .05). In conclusion, the present study shows that animals with a congenital nephron deficit have alterations in tubular sodium channels/transporters and cannot rapidly correct for variations in sodium intake probably contributing to the development of hypertension. This suggests that people born with a nephron deficit should be monitored for early signs of renal and cardiovascular disease.
Can adult cardiovascular disease be programmed in utero?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2006
mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans
Publisher: American Society for Clinical Investigation
Date: 19-09-2019
Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1161/HYPERTENSIONAHA.108.114058
Abstract: The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT 2 R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24±8 mm Hg versus 42±5 mm Hg P for the interaction between sex and treatment .002). Remarkably, low-dose angiotensin II decreased arterial pressure (11±4 mm Hg P for the interaction between sex and treatment .02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT 2 R blockade. Renal AT 2 R, angiotensin-converting enzyme 2, and left ventricular AT 2 R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT 2 R ratio of ≈1 in females. Angiotensin II infusion did not affect renal AT 2 R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (≈2.5 fold P for the interaction between sex and treatment .05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT 2 R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation.
Preglomerular and postglomerular resistance responses to different levels of sympathetic activation by hypoxia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2002
DOI: 10.1681/ASN.V13127
Improvement in Renal Hemodynamics following Combined Angiotensin II Infusion and AT1R Blockade in Aged Female Sheep following Fetal Unilateral Nephrectomy
Publisher: Public Library of Science (PLoS)
Date: 07-2013
Renal denervation potentiates the natriuretic and diuretic effects of atrial natriuretic peptide in anaesthetized rabbits.
Publisher: Wiley
Date: 1994
DOI: 10.1111/J.1440-1681.1994.TB02434.X
Abstract: 1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 microgram/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 +/- 3.11 mumol/min in response to ANP (approximately 55%, P < 0.05) compared to 0.84 +/- 0.59 mumol/min (approximately 28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 +/- 29.9 mumol/min (approximately 60%, P < 0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P < 0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.
Contribution of the Renal Nerves to Hypertension in a Rabbit Model of Chronic Kidney Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2020
DOI: 10.1161/HYPERTENSIONAHA.120.15769
Abstract: Overactivity of the sympathetic nervous system and high blood pressure are implicated in the development and progression of chronic kidney disease (CKD) and independently predict cardiovascular events in end-stage renal disease. To assess the role of renal nerves, we determined whether renal denervation (RDN) altered the hypertension and sympathoexcitation associated with a rabbit model of CKD. The model involves glomerular layer lesioning and uninephrectomy, resulting in renal function reduced by one-third and diuresis. After 3-week CKD, blood pressure was 13±2 mm Hg higher than at baseline ( P .001), and compared with sham control rabbits, renal sympathetic nerve activity was 1.2±0.5 normalized units greater ( P =0.01). The depressor response to ganglion blockade was also +8.0±3 mm Hg greater, but total norepinephrine spillover was 8.7±3.7 ng/min lower (both P .05). RDN CKD rabbits only increased blood pressure by 8.0±1.5 mm Hg. Renal sympathetic activity, the response to ganglion blockade and diuresis were similar to sham denervated rabbits (non-CKD). CKD rabbits had intact renal sympathetic baroreflex gain and range, as well as normal sympathetic responses to airjet stress. However, hypoxia-induced sympathoexcitation was reduced by −9±0.4 normalized units. RDN did not alter the sympathetic response to hypoxia or airjet stress. CKD increased oxidative stress markers Nox5 and MCP-1 (monocyte chemoattractant protein-1) in the kidney, but RDN had no effect on these measures. Thus, RDN is an effective treatment for hypertension in this model of CKD without further impairing renal function or altering the normal sympathetic reflex responses to various environmental stimuli.
Update on the angiotensin AT2 receptor
Publisher: Springer Science and Business Media LLC
Date: 06-12-2013
DOI: 10.1007/S11906-012-0321-4
Abstract: It is quite well established that activation of the AT(2) receptor (AT(2)R) provides a counter-regulatory role to AT(1)R overactivity, particularly during pathological conditions. Indeed, a potential therapeutic role for the AT(2)R is currently being promulgated with the introduction of novel AT(2)R ligands such as compound 21 (C21). In this brief review, we will focus on recent evidence to suggest that AT(2)R exhibits promising organ protection in the context of the heart, kidney and brain, with inflammation and gender influencing outcome. However, this field is not without controversy since the 'flagship' ligand C21 has also come under scrutiny, although it is safe to say there is much evidence to support a potentially important role of AT(2)R in a number of cardiovascular diseases. This report updates recent data in this field.
beta-Pro7Ang III is a novel highly selective angiotensin II type 2 receptor (AT2R) agonist, which acts as a vasodepressor agent via the AT2R in conscious spontaneously hypertensive rats
Publisher: Portland Press Ltd.
Date: 22-06-2015
DOI: 10.1042/CS20150077
Abstract: We have previously shown that in idual β-amino acid substitution in angiotensin (Ang) II reduced Ang II type 1 receptor (AT1R) but not Ang II type 2 receptor (AT2R)-binding and that the heptapeptide Ang III exhibited greater AT2R:AT1R selectivity than Ang II. Therefore, we hypothesized that β-amino-acid-substituted Ang III peptide analogues would yield highly selective AT2R ligands, which we have tested in binding and functional vascular assays. In competition binding experiments using either AT1R- or AT2R-transfected human embryonic kidney (HEK)-293 cells, novel β-substituted Ang III analogues lacked appreciable AT1R affinity, whereas most compounds could fully displace 125I-Sar1Ile8 Ang II from AT2R. The rank order of affinity at AT2R was CGP42112 & Ang III & β-Pro7 Ang III=Ang II & β-Tyr4 Ang III ≥ PD123319 & & β-Phe8 Ang III & & β Arg2 Ang III=β-Val3 Ang III & & β-Ile5 Ang III. The novel analogue β-Pro7 Ang III was the most selective AT2R ligand tested, which was & 000-fold more selective for AT2R than AT1R. IC50 values at AT2R from binding studies correlated with maximum vasorelaxation in mouse aortic rings. Given that β-Pro7 Ang III was an AT2R agonist, we compared β-Pro7 Ang III and native Ang III for their ability to reduce blood pressure in separate groups of conscious spontaneously hypertensive rats. Whereas Ang III alone increased mean arterial pressure (MAP), β-Pro7 Ang III had no effect. During low-level AT1R blockade, both Ang III and β-Pro7 Ang III, but not Ang II, lowered MAP (by ∼30 mmHg) at equimolar infusions (150 pmol/kg/min for 4 h) and these depressor effects were abolished by the co-administration of the AT2R antagonist PD123319. Thus, β-Pro7 Ang III has remarkable AT2R selectivity determined in binding and functional studies and will be a valuable research tool for insight into AT2R function and for future drug development.
Compensatory responses to nephron deficiency: adaptive or maladaptive?
Publisher: Wiley
Date: 17-02-2014
DOI: 10.1111/NEP.12198
Abstract: Compensatory renal growth is a characteristic adaptation to reduced renal mass that appears to recapitulate the normal pattern of maturation of the kidney during the postnatal period. Hypertrophy of tubules (predominantly the proximal tubule) and glomeruli is accompanied by increased single nephron glomerular filtration rate and tubular reabsorption of sodium. We propose that the very factors, which contribute to the increase in growth and function of the renal tubular system, are, in the long term, the precursors to the development of hypertension in those with a nephron deficit. The increase in single nephron glomerular filtration rate is dependent on multiple factors, including reduced renal vascular resistance associated with an increased influence of nitric oxide, and a rightward shift in the tubuloglomerular feedback curve, both of which contribute to the normal maturation of renal function. The increased influence of nitric oxide appears to contribute to the reduction in tubuloglomerular feedback sensitivity and facilitate the initial increase in glomerular filtration rate. The increased single-nephron filtered load associated with nephron deficiency may promote hypertrophy of the proximal tubule and so increased reabsorption of sodium, and thus a rightward shift in the pressure natriuresis relationship. Normalization of sodium balance can then only occur at the expense of chronically increased arterial pressure. Therefore, alterations/adaptations in tubules and glomeruli in response to nephron deficiency may increase the risk of hypertension and renal disease in the long-term.
Metalloendopeptidases EC 3.4.24.15 and EC 3.4.24.16 And Bradykinin B2 Receptors Do Not Play Important Roles In Renal Wrap Hypertension In Rabbits
Publisher: Wiley
Date: 30-10-2001
DOI: 10.1046/J.1440-1681.2001.03532.X
Abstract: 1. The aim of the present study was to determine the effects of the metalloendopeptidase (EP) 24.15 and 24.16 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) on haemodynamics and renal function in conscious rabbits with two-kidney, two-wrapped hypertension. We have also examined the role of endogenous bradykinin in the maintenance phase of this form of renovascular hypertension and whether inhibition of bradykinin degradation contributes to any potential effects of JA-2. 2. In two preliminary operations, rabbits were equipped with transit-time ultrasound flow probes for measuring cardiac output (CO) and renal blood flow (RBF) and had both kidneys wrapped in cellophane. Starting 4 weeks after the last operation, rabbits underwent four studies (3-5 days apart), during which they were treated with combinations of the bradykinin B2 receptor antagonist icatibant or its vehicle (1 mL/kg bodyweight 0.9% w/v NaCl) and JA-2 or its vehicle (1 mL/kg of a 5% w/v 2-hydroxypropyl-beta-cyclodextrin, 2.5% v/v dimethylsulphoxide solution). Renal function was monitored using standard renal clearance methods. 3. Icatibant (10 microg/kg) had no significant effects on systemic haemodynamic variables (mean arterial pressure, heart rate or CO), renal haemodynamic variables (RBF or glomerular filtration rate), urine flow or sodium excretion. At 5 mg/kg plus 3 mg/kg per h, JA-2 also did not affect any of these variables, either after icatibant vehicle treatment or after icatibant treatment. 4. Our data do not support major roles for endogenous bradykinin or bradykinin degradation by EP 24.15/24.16 in the control of systemic and renal haemodynamics or renal excretory function in two-kidney, two-wrapped hypertension in rabbits.
Angiotensin-Based Peptides as AT2R Agonists
Publisher: Elsevier
Date: 2015
Sex-Specific Influence of Angiotensin Type 2 Receptor Stimulation on Renal Function
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
DOI: 10.1161/HYPERTENSIONAHA.111.184986
Abstract: The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11- to 12-week–old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1±2.4% versus females: 23.0±3.2% change in renal blood flow at 300 ng/kg per minute versus baseline P .01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females ( P Group =0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women.
Glomerular surface area is normalized in mice born with a nephron deficit: no role for AT1receptors
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPRENAL.90359.2008
Abstract: We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with ∼30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 (AT 1 )-receptor antagonist candesartan (Cand 10 mg·kg −1 ·day −1 ) from 5 wk of age to determine the role of AT 1 receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (∼45%) less than that of WT mice ( P 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20–30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require AT 1 receptor activation.
High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/AJPRENAL.00049.2010
Abstract: The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the “first hit” and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 ± 1, 103 ± 1, and 102 ± 2 mmHg). On a high-salt diet, MAP increased 9.1 ± 1.9 mmHg in HET1K mice ( P 0.05) and 5.4 ± 0.9 mmHg in HET2K mice ( P 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype.
You are what you drink! focus on “rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury”
Publisher: American Physiological Society
Date: 07-2016
Chronic angiotensin converting enzyme inhibition enhances renal vascular responsiveness to acetylcholine in anaesthetized rabbits
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-0010
DOI: 10.1097/00004872-200108000-00019
Abstract: To determine whether 6 weeks continuous treatment with an angiotensin converting enzyme (ACE) inhibitor reduced renal vascular responsiveness in vivo, since this treatment results in extensive phenotypic conversion of afferent arteriolar cells from contractile to endocrine-like, renin secretory cells. Enalapril (10 microg/kg per h s.c.) was delivered continuously for 6 weeks. In anaesthetized rabbits (treated or sham), arterial blood pressure and renal blood flow were measured and renal responsiveness tested by constructing dose-response curves to bolus doses of phenylephrine, angiotensin II and acetylcholine delivered directly into the renal artery. ACE inhibition resulted in a significant shift to the left in the renal vascular conductance responses to acetylcholine (P < 0.005) and angiotensin II (P < 0.05), indicating enhanced, not reduced, responsiveness to these agents. There were no significant effects of chronic ACE inhibition on the conductance responses to phenylephrine. Contrary to our hypothesis, 6 weeks ACE inhibition did not reduce renal vascular responsiveness to three vasoactive agents, suggesting that the phenotypic changes observed in the afferent arterioles and to a lesser extent the interlobular arteries, were either insignificant or compensated for by other changes in renal circulatory control.
The renin-angiotensin system: New horizons
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2011
Undergraduate perceptions of human and anesthetised rabbit cardiovascular physiology practicals
Publisher: Wiley
Date: 04-2013
High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/682745
Abstract: Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT 2 R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT 2 R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For ex le, at 300 ng kg −1 min −1 , Ang II reduced RBF by 45.7 ± 1.9 % in estradiol-treated rats but only by 27.3 ± 5.1 % in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT 2 R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.
The Novel AT2 Receptor Agonist β-Pro7-AngIII Exerts Cardiac and Renal Anti-Fibrotic and Anti-Inflammatory Effects in High Salt-Fed Mice
Publisher: MDPI AG
Date: 14-11-2022
Abstract: A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT2R) has been considered as organ protective in many CVDs. However, there are limited AT2R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro7-AngIII, showed high selectivity for the AT2R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT2R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks’ treatment (from weeks 5–8) with β-Pro7-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro7-AngIII were attenuated by the AT2R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT2R-selective β-Pro7-AngIII, highlighting it as an important therapeutic that can target the AT2R to treat end-organ damage.
Adult Rabbit Offspring of Mothers With Secondary Hypertension Have Increased Blood Pressure
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
DOI: 10.1161/01.HYP.0000052949.85257.8E
Abstract: Preexisting chronic hypertension complicates up to 5% of pregnancies and is associated with an increased risk of low-birth-weight babies. Studies suggest that an adverse intrauterine environment leading to low birth weight is linked to an increased risk of cardiovascular disease, including hypertension, in the adult. In this study, the blood pressure of offspring from mothers with hypertension were followed up into adulthood. Two-kidney, 1-wrapped hypertension was induced in 7 female rabbits 5 other rabbits underwent sham surgery. Four weeks later, rabbits were mated, at which time mean arterial pressure was 118±3 and 87±5 mm Hg in the hypertensive and sham groups, respectively ( P .001). The blood pressure of 30-week-old females was 89±2 mm Hg in the offspring of hypertensive (n=14) and 79±1 mm Hg in the offspring of normotensive (n=13) mothers ( P .005). Also, plasma renin activity was significantly lower in the female offspring of hypertensive mothers at 10 weeks of age ( P .05), suggesting that development of the renin-angiotensin system was altered. In contrast, male offspring from hypertensive and normotensive mothers had similar mean arterial pressure and plasma renin activity. In conclusion, maternal secondary hypertension can “program” hypertension in female adult offspring. The results also suggest that there are gender-specific differences in sensitivity to altered in utero environmental influences.
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