ORCID Profile
0000-0002-9253-3773
Current Organisations
Macquarie University
,
University of Melbourne
,
Monash University
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Publisher: S. Karger AG
Date: 2002
DOI: 10.1159/000049431
Abstract: i Background/Aims: /i A reduction in nephron endowment leading to reduced renal filtration surface area has been implicated in the development of hypertension. The aim of this study was to compare glomerular (and thereby nephron) number and renal filtration surface area in young Wistar-Kyoto rats (WKY) with young spontaneously hypertensive rats (SHR), prior to the development of hypertension in this model. i Methods: /i Using unbiased stereological methods the number and size of glomeruli, as well as total renal filtration surface area were determined in perfusion-fixed kidneys of 4-week-old WKY and SHR. i Results: /i At 4 weeks of age, in weight-matched animals, there was no significant difference in the number of glomeruli in the kidneys of SHR compared to WKY (28,620 ± 1,643 and 25,670 ± 1,263 glomeruli/kidney, respectively). Similarly, there was no difference in mean glomerular volume (SHR: 4.70 ± 0.31 × 10 sup –4 /sup mm sup /sup WKY: 4.28 ± 0.20 × 10 sup –4 /sup mm sup /sup ). Surprisingly, total renal filtration surface area was significantly greater in SHR than WKY (3,867 ± 116 and 3,176 ± 83 mm sup /sup , respectively). i Conclusion: /i The renal abnormality underlying the development of hypertension in the SHR is not due to inborn deficits in nephron endowment and/or filtration surface area.
Publisher: American Physiological Society
Date: 12-2009
DOI: 10.1152/AJPRENAL.00163.2009
Abstract: Nephrogenesis occurs predominantly in late gestation at a time when preterm infants are already delivered. The aims of this study were to assess the effect of preterm birth and the effect of antenatal glucocorticoid treatment on nephrogenesis. Preterm baboons, which were delivered at 125 days gestation and ventilated for up to 21 days postnatally, were compared with gestational controls. A cohort of preterm baboons that had been exposed to antenatal glucocorticoids were compared with unexposed preterm baboons. The number of glomerular generations was estimated using a medullary ray glomerular-counting method, and glomerular number was estimated using unbiased stereology. CD31 and WT-1 localization was examined using immunohistochemistry and VEGF was localized using in situ hybridization. The number of glomerular generations was not affected by preterm birth, and total glomerular numbers were within the normal range. Kidneys were significantly enlarged in preterm baboons with a significant decrease in glomerular density (number of glomeruli per gram of kidney) in the preterm kidney compared with gestational controls. Neonates exposed to antenatal steroids had an increased kidney-to-body weight ratio and also more developed glomeruli compared with unexposed controls. Abnormal glomeruli, with a cystic Bowman's space and shrunken glomerular tuft, were often present in the superficial renal cortex of both the steroid-exposed and unexposed preterm kidneys steroid exposure had no significant effect on the proportion of abnormal glomeruli. The proportion of abnormal glomeruli in the preterm kidneys ranged from 0.2 to 18%. In conclusion, although nephrogenesis is ongoing in the extrauterine environment, our findings demonstrate that preterm birth, independent of steroid exposure, is associated with a high proportion of abnormal glomeruli in some, but not all neonatal kidneys. Whether final nephron endowment is affected in those kidneys exhibiting a high proportion of abnormal glomeruli is yet to be confirmed.
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.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/412831
Abstract: Preterm birth is a major cause of perinatal mortality and long-term morbidity. Chorioamnionitis is a common cause of preterm birth. Clinical chorioamnionitis, characterised by maternal fever, leukocytosis, tachycardia, uterine tenderness, and preterm rupture of membranes, is less common than subclinical/histologic chorioamnionitis, which is asymptomatic and defined by inflammation of the chorion, amnion, and placenta. Chorioamnionitis is often associated with a fetal inflammatory response. The fetal inflammatory response syndrome (FIRS) is defined by increased systemic inflammatory cytokine concentrations, funisitis, and fetal vasculitis. Clinical and epidemiological studies have demonstrated that FIRS leads to poor cardiorespiratory, neurological, and renal outcomes. These observations are further supported by experimental studies that have improved our understanding of the mechanisms responsible for these outcomes. This paper outlines clinical and experimental studies that have improved our current understanding of the mechanisms responsible for chorioamnionitis-induced preterm birth and explores the cellular and physiological mechanisms underlying poor cardiorespiratory, neural, retinal, and renal outcomes observed in preterm infants exposed to chorioamnionitis.
Publisher: Elsevier BV
Date: 07-1990
Publisher: Public Library of Science (PLoS)
Date: 24-02-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-12-1998
DOI: 10.1161/01.CIR.98.23.2621
Abstract: Background —The detrimental effects of high dietary salt intake may not only involve effects on blood pressure and organ hypertrophy but also lead to tissue fibrosis independently of these factors. Methods and Results —The effect of a normal (1%) or high (8%) sodium chloride diet on myocardial and renal fibrosis was assessed by quantitative histomorphometry in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The effect of salt on transforming growth factor-β 1 (TGF-β 1 ) gene expression was assessed by Northern blot hybridization. A high-salt diet from 8 to 16 weeks of age resulted in increased blood pressure and left ventricular and renal hypertrophy in both WKYs and SHRs. Marked interstitial fibrosis was demonstrated in the left ventricle (LV), glomeruli, and renal tubules and in intramyocardial arteries and arterioles but not in the right ventricle. The collagen volume fraction increased significantly after high-salt diet in the LV, intramyocardial arteries and arterioles, glomeruli, and peritubular areas in both WKYs and SHRs. In the kidneys, glomerular and peritubular type IV collagen was also increased. There was overexpression of TGF-β 1 mRNA in the LV and kidneys in both rat strains after a high-salt diet (all P .001). Conclusions —High dietary salt led to widespread fibrosis and increased TGF-β 1 in the heart and kidney in normotensive and hypertensive rats. These results suggest a specific effect of dietary salt on fibrosis, possibly via TGF-β 1 –dependent pathways, and further suggest that excessive salt intake may be an important direct pathogenic factor for cardiovascular disease.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2018
DOI: 10.1038/PR.2017.324
Abstract: BackgroundGlobally, ∼10% of infants are born before full term. Preterm birth exposes the heart to the demands of postnatal cardiovascular function before cardiac development is complete. Our aim was to examine, in hearts collected from infants at autopsy, the effects of preterm birth on myocardial structure and on cardiomyocyte development.Methods and resultsHeart tissue was collected at perinatal autopsies of 16 infants who died following preterm birth between 23 and 36 weeks of gestation, and survived for 1-42 days the hearts of 37 appropriately grown stillborn infants, aged 20-40 weeks of gestation, were used for comparison. Using confocal microscopy and image analysis, cardiomyocyte proliferation, maturation, ploidy, and size were quantified, and interstitial collagen and myocardial capillarization were measured. Preterm birth resulted in a marked reduction in the proliferation of cardiomyocytes relative to age-matched stillborn infant controls (preterm vs. control P<0.0001). In contrast, preterm birth did not affect heart weight, capillarization, interstitial collagen or cardiomyocyte maturation, ploidy, and size.ConclusionsPreterm birth appears to lead to an abrupt reduction in cardiomyocyte cell ision. This reduced cardiomyocyte proliferation in preterm infants may adversely impact upon the final number of cardiomyocytes which may reduce cardiac functional reserve, and impair the reparative capacity of the myocardium.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2001
DOI: 10.1097/00004872-200104000-00016
Abstract: To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances myocardial vascularization in adolescent and adult spontaneously hypertensive rats (SHRs). Male SHRs were treated from 7 to 14 or from 16 to 24 weeks of age with the ACE inhibitor, perindopril, in either a low dose (0.1 mg/kg per day) or a high dose (1 mg/kg per day). Some rats were concomitantly treated with a bradykinin antagonist. At termination of treatment, the left ventricular wall was extensively s led and the surface area density and length density of myocardial blood vessels stereologically determined. High-dose perindopril treatment prevented the development of hypertension and left ventricular hypertrophy in adolescent SHRs and markedly reduced blood pressure and left ventricular size in adult SHRs. SHRs treated with the low dose of perindopril remained hypertensive, although there were significant reductions in blood pressure and left ventricular growth. High-dose perindopril treatment in adolescent SHRs led to a significant increase in the surface area density of blood vessels in the left ventricle after 4 weeks of treatment and an increase in both the surface area density and length density of blood vessels after 7 weeks of treatment Co-administration with the bradykinin antagonist did not reverse these effects. In contrast, ACE inhibitor treatment had no effect on myocardial vascularization in adult rats with established hypertension. ACE inhibitor treatment enhances vascularization in the adolescent heart through reductions in myocardial mass, but not capillary growth. ACE inhibition in the adult heart with established hypertension reduces left ventricular hypertrophy, but does not enhance myocardial capillarization.
Publisher: Springer Science and Business Media LLC
Date: 05-2004
Publisher: Springer Science and Business Media LLC
Date: 22-09-2005
DOI: 10.1007/S00418-005-0072-2
Abstract: CD34 is a positive marker for haematopoietic stem cells and endothelial cells. Recent evidence suggests that haematopoietic progenitor cells are involved in atherogenesis. CD34-positive haematopoietic progenitor cells have never been described in rabbit atherosclerotic tissues. The aim of this study is to identify CD34-positive haematopoietic progenitor cells in rabbit atherosclerotic tissues, and to compare this with macrophage (RAM-11), alpha smooth muscle cell actin and fibroblast (prolyl-4-hydroxylase) immunoreactive cells. Sixteen Male New Zealand White rabbits were ided into two groups: Group 1, control diet (Con) group 2, 0.5% cholesterol diet, and killed after 12 weeks. Immunohistochemistry was used to detect CD34 haematopoietic progenitor cells. CD34-positive haematopoietic progenitor cells were identified both within and overlying atherosclerotic plaques. As well, these haematopoietic progenitor cells also stained for RAM-11, CD45, prolyl-4 hydroxylase and alpha smooth muscle cell actin. These findings suggest that in the rabbit model of atherosclerosis, the previously identified macrophages, smooth muscle cells and fibroblasts within and overlying atherosclerotic plaques might be of haematopoietic origin.
Publisher: Wiley
Date: 07-01-2019
DOI: 10.1002/AR.24037
Abstract: Capillarization plays a key role in the growth of the developing heart. We therefore hypothesized that impaired heart development following intrauterine growth restriction (IUGR) may arise from inadequate myocardial capillary growth. The aims of the study were to examine the effect of IUGR on the growth and diffusion radius of intramyocardial capillaries in rats at postnatal day 1. Uteroplacental insufficiency was induced in rats in late gestation (E18, term = E22) by bilateral uterine artery and vein ligation (restricted offspring N = 12 six males and six females) offspring from sham‐operated dams were used as controls (N = 10 five males and five females). At postnatal day 1, the hearts were immersion‐fixed and heart volume, capillary length density, capillary diffusion radius, and total capillary length were stereologically determined. Restricted offspring were significantly smaller at birth, with a concomitant reduction in heart volume and total myocardial capillary length compared to controls. Capillary growth was not impaired relative to heart size, with no significant differences in capillary length density or diffusion radius in the myocardium of restricted and control offspring. There were no sex differences in any of the parameters examined. In conclusion, there was no evidence to indicate that microvascular development is compromised in the heart of IUGR offspring at 1 day after birth. Total myocardial capillary length, however, was significantly reduced in the growth restricted offspring and further longitudinal studies are required to elucidate the long‐term impact, particularly following hypertrophic cardiac growth. Anat Rec, 302:1580–1586, 2019. © 2018 American Association for Anatomy
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPRENAL.00066.2011
Abstract: Chorioamnionitis is an antecedent of preterm birth. We aimed to determine the effect of experimental chorioamnionitis in fetal sheep during late gestation on 1) nephron number, 2) renal corpuscle volume, and 3) renal inflammation. We hypothesized that exposure to chorioamnionitis would lead to inflammation in fetal kidneys and adversely impact on the development of nephrons, leading to a reduction in nephron number. At ∼121 days of gestation (term ∼147 days), pregnant ewes bearing twin or singleton fetuses received a single intra-amniotic injection of lipopolysaccharide ( n = 6 3 singletons, 3 twins) controls were either untreated or received an intra-amniotic injection of saline ( n = 8 4 singletons, 4 twins). One twin was used from each twin-bearing ewe. At ∼128 days of gestation, fetuses were delivered via Caesarean section. Kidneys were collected and stereologically analyzed to determine nephron number and renal corpuscle volume. Renal inflammation was assessed using immunohistochemistry. Experimental chorioamnionitis did not affect body weight or relative kidney weight. There was a significant reduction in nephron number but no change in renal corpuscle volume in LPS-exposed fetuses relative to controls. On average, nephron number was significantly reduced by 23 and 18% in singleton and twin LPS-exposed fetuses, respectively. The degree of renal inflammation did not differ between groups. Importantly, this study demonstrates that exposure to experimental chorioamnionitis adversely impacts on nephron number in the developing fetus.
Publisher: Elsevier BV
Date: 06-1993
DOI: 10.1016/0002-9149(93)90947-B
Abstract: The aim was to determine whether cardiovascular hypertrophy in primary hypertension in the spontaneously hypertensive rat (SHR) is induced by increased levels of angiotensin II or by increased blood pressure. SHR were treated from 7 to 15 weeks of age with perindopril to block the in vivo production of A II and concomitantly infused with either a pressor dose of norepinephrine or angiotensin II. At the end of the treatment period, there was no significant difference in the systolic blood pressure in the norepinephrine or angiotensin II-treated groups (201 +/- 9 and 208 +/- 8 mm Hg, respectively). However, there was a significant increase (p < 0.01) in left ventricle-plus-septum/body weight ratio in angiotensin II compared with norepinephrine-infused SHR (3.72 +/- 0.25 and 2.34 +/- 0.04 mg/g, respectively) and in aortic medial cross-sectional area (0.55 +/- 0.05 and 0.38 +/- 0.01 mm2, respectively). Using an unbiased optical dissector/fractionator technique, the number of smooth muscle cells in the descending thoracic aorta of the angiotensin II-infused SHR was not different from norepinephrine-infused rats (5.02 +/- 0.30 x 10(6) and 4.71 +/- 0.42 x 10(6) cells, respectively), and no difference in size of enzyme-isolated cells was observed (mode: 1,326 +/- 127 microns 3 compared with 1,186 +/- 82 microns 3). The results indicate that angiotensin II directly stimulates cardiac and aortic hypertrophy through a mechanism unrelated to its effect on blood pressure. The aortic hypertrophy is not due to an increase in smooth muscle cell size or number and thus must be related to an increase in the extracellular compartment.
Publisher: Oxford University Press (OUP)
Date: 07-05-2010
Abstract: Pre-term birth affects 10-12% of live births and occurs when the myocardium is still developing therefore, the final structure of the myocardium could be altered. We hypothesized that, in response to pre-term birth, structural remodelling occurs within the myocardium which enables the immature heart muscle to adapt to the haemodynamic transition at birth but results in persistent alterations in its structure. Our objective was to determine how pre-term birth alters the final structure of the myocardium. Using sheep, pre-term birth was induced at 0.9 of term hearts were examined at 9 weeks after term-equivalent age, when cardiomyocyte proliferation and maturation have ceased. In pre-term lambs, we found that cardiomyocytes of both ventricles and the interventricular septum were hypertrophied. Cardiomyocyte maturation in pre-term lambs was altered in that there was a greater proportion of mononucleated, polyploid (4n) cardiomyocytes in both ventricles compared with controls importantly, induction of polyploidy is associated with irreversible stress-related changes in DNA. We also found a six- to seven-fold increase in collagen deposition, usually accompanied by lymphocytic infiltration. We conclude that pre-term birth leads to remodelling of the myocardium that alters its final structure. This may programme for long-term cardiac vulnerability.
Publisher: Springer Science and Business Media LLC
Date: 2008
DOI: 10.1007/S00467-007-0641-9
Abstract: There is increasing evidence of vitamin D insufficiency in women of child-bearing age and their infants. This study examined the effect of maternal vitamin D deficiency on nephron endowment in rat offspring (n=7 per group). Sprague-Dawley dams were fed either a vitamin D deplete diet or a vitamin replete (control) diet prior to pregnancy, during pregnancy and throughout lactation. At 4 weeks of age the offspring were weaned and maintained on their respective diets until they were killed at 7 weeks. In the fixed right kidney, kidney volume, renal corpuscle volume and nephron number were stereologically determined. There was no difference between groups in body weight, kidney weight or kidney volume. There was a significant 20% increase in nephron number in kidneys of vitamin D deplete offspring (vitamin D deficient, 29,000+/-1,858, control, 23,330+/-1,828 P=0.04). This was accompanied by a significant decrease in renal corpuscle size in the vitamin D deplete group compared with the controls (6.125+/-0.576 x 10(-4) mm(3) and 8.178+/-0.247 x 10(-4) mm(3), respectively P=0.03). We concluded that maternal vitamin D deficiency in rats appears to stimulate nephrogenesis. Whether this confers a renal functional advantage or not is unknown.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2011
Publisher: Springer Science and Business Media LLC
Date: 07-2006
DOI: 10.1203/01.PDR.0000220361.08181.C3
Abstract: This study examines the effect of maternal protein restriction in rats on levels of cardiac fibrosis, myocardial capillarization, and media:lumen ratio of intramyocardial arteries in adult offspring. Female Wistar Kyoto rats were fed either a normal protein diet (NPD 20% casein) or a low-protein diet (LPD 8.7% casein) during pregnancy and lactation. Female offspring (seven per group) were weaned at 4 wk of age and grown to adulthood. At 24 wk of age, the offspring were perfusion fixed. Cardiac fibrosis and media:lumen ratio of intramyocardial arterioles was assessed using image analysis and cardiac capillarization was stereologically investigated. Body weights at 2 and 24 wk of age were significantly reduced (31% and 8%, respectively) in the LPD offspring however, heart size was not different at 24 wk. Importantly by adulthood, there was a significant 15% increase in left ventricular interstitial fibrosis in LPD offspring. There were no differences in levels of perivascular fibrosis, myocardial capillarization, or in the media:lumen ratio of intramyocardial arteries between groups. Because cardiac fibrosis is associated with impaired cardiac contractility and arrhythmia, our results suggest that induction of interstitial fibrosis may contribute to the increased cardiac disease in adult subjects who were exposed to an adverse intrauterine environment.
Publisher: BMJ
Date: 08-2015
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.CLP.2014.05.006
Abstract: The normal development of the kidney may be affected by several factors, including abnormalities in placental function, resulting in fetal growth restriction, exposure to maternal disease states, including hypertension and diabetes, antenatal steroids, chorioamnionitis, and preterm delivery. After preterm birth, several further insults may occur that may influence nephrogenesis and renal health, including exposure to nephrotoxic medications, postnatal growth failure, and obesity after growth restriction. In this review article, common clinical neonatal scenarios are used to highlight these renal risk factors, and the animal and human evidence on which these risk factors are based are discussed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 16-01-2023
Publisher: Elsevier BV
Date: 02-2004
Publisher: Springer Science and Business Media LLC
Date: 21-12-2011
DOI: 10.1038/PR.2011.29
Abstract: Preterm birth affects 8-12% of live births and is associated with the development of elevated arterial blood pressure and aortic narrowing in later life this suggests that preterm birth may alter the development of arteries. Our objective was to determine the effects of preterm birth, accompanied by antenatal corticosteroid administration, on the structure of the aorta and pulmonary artery, which experience different alterations in pressure flow at birth. At 11 wk, preterm lambs had significantly thicker aortic walls and a smaller lumen, whereas the morphometry of the pulmonary artery was unaffected. Elastin deposition was markedly increased in the aorta and pulmonary artery and smooth muscle content was reduced in the aorta only. In preterm lambs we found injury in the aorta only controls were unaffected. We conclude that moderate preterm birth after antenatal betamethasone can cause injury and persistent alterations in the structure and composition of the aorta, with lesser effects in the pulmonary artery. Our findings suggest that preterm birth may increase the risk of atherosclerosis and aortic aneurysms in later life. Using an established ovine model of preterm birth, lambs were born at 0.9 of gestation and underwent necropsy at 11 wk after birth controls were born at term.
Publisher: Wiley
Date: 27-10-2013
Publisher: Wiley
Date: 26-01-2007
Publisher: Wiley
Date: 21-07-2020
DOI: 10.1002/AR.24484
Publisher: Springer Science and Business Media LLC
Date: 11-2011
DOI: 10.1038/PR.2011.516
Publisher: Wiley
Date: 03-1994
DOI: 10.1111/J.1440-1681.1994.TB02507.X
Abstract: 1. The incidence of aortic smooth muscle cell polyploidy was investigated in rabbits and rats with renal wrap induced (cellophane perinephritic) chronic hypertension. 2. Bilateral renal cellophane wrapping was performed in young adult animals. Blood pressure was measured intra-arterially in the rabbits twice during the experimental period and tail-cuff blood pressure measured twice weekly in the rats. At 8 weeks post-surgery the incidence of aortic smooth muscle cell polyploidy was determined in enzymatically isolated cells by flow cytometric DNA analysis. 3. Systolic blood pressure was significantly increased in the bilateral renal wrapped rabbits and rats compared to the shams, such that at 8 weeks post-surgery, systolic blood pressure was 139 +/- 2 mmHg and 84 +/- 2 mmHg, respectively, in the rabbits and 188 +/- 6 mmHg and 155 +/- 4 mmHg, respectively, in the rats. 4. The incidence of polyploid smooth muscle cells was significantly higher in the hypertensive renal wrapped rat compared to the sham (20.9 +/- 1.5% and 8.1 +/- 0.5%, respectively). However, the incidence of polyploid cells was low in the rabbit aortae with no significant difference in the incidence of aortic smooth muscle polyploidy in the hypertensive rabbit compared to the sham (2.6 +/- 0.6% and 2.7 +/- 0.6%, respectively). 5. This study demonstrates a species difference in the induction of polyploidy during the same model of experimental hypertension in aortic smooth muscle derived from the rabbit and rat.
Publisher: Frontiers Media SA
Date: 29-01-2018
Publisher: Springer Science and Business Media LLC
Date: 12-02-2008
DOI: 10.1007/S00418-008-0398-7
Abstract: The baboon is an ideal animal model to study human kidney development. The aim of the current study was to use immunohistochemistry to localise the antigens TRA-1-60, TRA-1-81, GCTM-2 and podocalyxin in the developing baboon kidney where nephrogenesis was still on-going and in kidneys where nephrogenesis was complete. Fixed kidney sections from baboons delivered at 125, 140, 175 and 185 days gestation (term = 185 days) were immuno-labelled with antibodies directed against TRA-1-60, TRA-1-81, GCTM-2 and podocalyxin. In kidneys with on-going nephrogenesis (125 and 140 days gestation), TRA-1-60, TRA-1-81 and GCTM-2 were specifically localised to the apical plasma membrane of the epithelium of the ureteric ullae and the collecting ducts, while podocalyxin immunostaining was not detected. In kidneys where nephrogenesis was complete (175 and 185 days gestation) localisation of these markers was again very specifically localised to the collecting ducts. In conclusion, although further experimentation is required to confirm the identity of the specific cell types marked by these antibodies, this study provides new insight into the distribution of commonly utilised stem cell antibodies in the developing baboon kidney.
Publisher: Wiley
Date: 21-01-2020
DOI: 10.1002/AR.24361
Abstract: The evaluation of a range of measures in the kidneys, such as developmental stage, rate and success, injury, and disease processes, relies on obtaining information on the three-dimensional structure of the renal corpuscles, and in particular the glomerular capillary tufts. To do this in the most accurate, comprehensive, and unbiased manner depends on a knowledge of stereological methods. In this article, we provide a practical guide for researchers on how to quantitate a number of structures in the kidneys, including the estimation of total glomerular number, glomerular capillary length and filtration surface area, and the cellular composition of in idual glomeruli. Guidance is also provided on how to apply these methods to kidneys at different sizes and levels of maturity.
Publisher: Wiley
Date: 07-2014
DOI: 10.14814/PHY2.12087
Publisher: Oxford University Press (OUP)
Date: 06-02-2015
DOI: 10.1093/CVR/CVV028
Abstract: Foetal growth has been proposed to influence cardiovascular health in adulthood, a process referred to as foetal programming. Indeed, intrauterine growth restriction in animal models alters heart size and cardiomyocyte number in the perinatal period, yet the consequences for the adult or challenged heart are largely unknown. The aim of this study was to elucidate postnatal myocardial growth pattern, left ventricular function, and stress response in the adult heart after neonatal cardiac hypoplasia in mice. Utilizing a new mouse model of impaired cardiac development leading to fully functional but hypoplastic hearts at birth, we show that myocardial mass is normalized until early adulthood by accelerated physiological cardiomyocyte hypertrophy. Compensatory hypertrophy, however, cannot be maintained upon ageing, resulting in reduced organ size without maladaptive myocardial remodelling. Angiotensin II stress revealed aberrant cardiomyocyte growth kinetics in adult hearts after neonatal hypoplasia compared with normally developed controls, characterized by reversible overshooting hypertrophy. This exaggerated growth mainly depends on STAT3, whose inhibition during angiotensin II treatment reduces left ventricular mass in both groups but causes contractile dysfunction in developmentally impaired hearts only. Whereas JAK/STAT3 inhibition reduces cardiomyocyte cross-sectional area in the latter, it prevents fibrosis in control hearts, indicating fundamentally different mechanisms of action. Impaired prenatal development leading to neonatal cardiac hypoplasia alters postnatal cardiac growth and stress response in vivo, thereby linking foetal programming to organ size control in the heart.
Publisher: Wiley
Date: 06-04-2018
DOI: 10.1113/JP275654
Publisher: Wiley
Date: 04-1988
DOI: 10.1111/J.1440-1681.1988.TB01085.X
Abstract: 1. Two groups of spontaneously hypertensive rats (SHR) were treated with enalapril (25-30 mg/kg per day): Group I received treatment from 4 to 14 weeks of age to inhibit development of hypertension and Group R received the drug from 14 to 20 weeks of age to reverse established hypertension. 2. Systolic blood pressure, ploidy of aortic smooth muscle cells (flow cytometric DNA analysis) and aortic hypertrophy (medial cross-sectional area) were determined at times both during and after enalapril treatment (up to 30 weeks). 3. Enalapril treatment normalized blood pressure to that of age-matched Wistar-Kyoto rats in both groups. Blood pressure rose again following cessation of treatment. 4. In untreated SHR the incidence of polyploid cells increased concomitantly with increasing pressure throughout the time studied, whereas in Group I the incidence remained low. In Group R, the incidence of polyploidy directly paralleled both the decrease (normalization) and the rise in blood pressure following cessation of treatment. 5. Hence, the incidence of vascular smooth muscle cell polyploidy is not simply a result of growth of the vessel with increasing age of the SHR, but parallels inhibition, reversal, and redevelopment of hypertension.
Publisher: Portland Press Ltd.
Date: 09-07-2014
DOI: 10.1042/CS20140097
Abstract: Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which might be explained by altered cardiomyocyte proliferation and maturation. Pregnant ewes received an ultrasound-guided intra-amniotic injection of lipopolysaccharide (LPS) or saline 7 days prior to delivery at day 127 of pregnancy (term 147 days). Cardiac contractility was recorded in spontaneously beating hearts of the offspring, perfused in a Langendorff apparatus. Saline-filled latex balloons were inserted into the left ventricle (LV) and right ventricle (RV). Responsiveness to isoprenaline and stop-flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed, and cardiomyocyte nuclearity, volume and number were determined. β-Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS-exposed fetuses, contractility in the LV and RV was suppressed by ~40% and cardiomyocyte numbers were reduced by ~25%. Immature mono-nucleated cardiomyocytes had lower volumes (~18%), whereas mature bi-nucleated cardiomyocyte volume was ~77% greater. Although basal coronary flow was significantly increased by 21±7% in LPS-exposed hearts, following ischaemia/reperfusion (IR), end-diastolic pressure was increased 2.4±0.3-fold and infarct area was increased 3.2±0.6-fold compared with those in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in β-adrenoceptor mRNA, suggesting altered second messenger signalling. Intrauterine inflammation altered cardiac growth, suppressed contractile function and enhanced responsiveness to stress. Although these effects may ensure immediate survival, they probably contribute to the increased vulnerability of organ perfusion in preterm neonates.
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.
Publisher: Springer Science and Business Media LLC
Date: 10-2011
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/543062
Abstract: Cardiac AT 2 R expression is upregulated in the normal process of aging. In this study we determined the contribution of AT 2 R to chronic antihypertensive and remodelling effects of AT 1 R blockade in aged hypertensive rats. Adult (20 weeks) and senescent (20 months) spontaneously hypertensive rats (SHRs) were treated with either the AT 1 R antagonist, candesartan cilexetil (2 mg/kg/day), the AT 2 R antagonist, PD123319 (10 mg/kg/day), or a combination of the 2 compounds. Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter. Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration. Vascular hypertrophy was reduced by candesartan cilexetil, and these effects were reversed by simultaneous PD123319. These results suggest that AT 2 R stimulation does not significantly influence the antihypertensive effect of chronic AT 1 R blockade, but plays a role in the regulation of vascular structure. The severe degree of cardiac perivascular fibrosis in senescent animals was regressed by AT 1 R blockade and this effect was reversed by simultaneous AT 2 R inhibition, demonstrating an antifibrotic role of AT 2 R stimulation in the aging hypertensive heart.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2012
DOI: 10.1038/PR.2012.94
Abstract: Intrauterine growth restriction (IUGR) has been linked to heart disease in adulthood. Hence the IUGR heart is likely to be vulnerable to diabetic heart disease. The aim of this study was to examine the effect of induction of type 1 diabetes on myocardial collagen deposition and cardiac function in adult rats with a history of IUGR, after controlling blood glucose levels. IUGR was induced by protein restriction in the pregnant female rat. When the offspring were 24 wk of age, diabetes was induced in male IUGR and non-IUGR rats by means of streptozotocin insulin injections were used to maintain blood glucose levels at a mild (7-10 mmol/l n = 8 per group) or moderate level (10-15 mmol/l n = 8 per group). Echocardiography and cardiac morphology analyses were carried out when the rats were 32 wk of age. IUGR offspring exhibited cardiac hypertrophy at 32 wk, including a thicker posterior wall and increased interstitial fibrosis in the left ventricle. Hyperglycemia led to an increase in heart size and myocardial fibrosis. The response to hyperglycemia was not different between IUGR and non-IUGR rats however, cardiac fibrosis was greatest when diabetes was present along with a history of IUGR. In general, maintaining blood glucose levels at a mildly hyperglycemic level attenuated the adverse effects of hyperglycemia but did not reverse the fibrosis. Exacerbated fibrosis in hyperglycemic hearts of IUGR offspring may lead to long-term cardiac dysfunction.
Publisher: American Medical Association (AMA)
Date: 06-06-2017
Publisher: SAGE Publications
Date: 02-2006
Abstract: In this study, caveolin-1 (cav-1), an inhibitor of endothelial nitric oxide synthase (eNOS), was semi-quantified in diseased human and rabbit blood vessels. New Zealand White rabbits were fed, for 12 weeks, a high methionine diet (to induce intimal hyperplasia), 0.5% cholesterol diet, a normal diet, or the combination of both experimental diets. Excess segments of human internal mammary arteries (IMA) and radial arteries (RA) were obtained from patients undergoing coronary artery bypass surgery. eNOS and cav-1 were localized throughout both human and rabbit vessels. In rabbit arteries, eNOS was significantly increased in the endothelium overlying intimal thickening and atherosclerotic plaques compared with the adjacent endothelium overlying normal media. Interestingly, the endothelial cav-1:eNOS ratio increased 5-fold only in endothelium overlying plaques but decreased in endothelium overlying vessels with neo-intimal thickening. In human tissue, there was no difference between RA and IMA eNOS immunoreactivity in endothelium, intima, or media however, RA endothelial, intimal, and medial cav-1 immunoreactivity increased 4-fold ( p, .02), 8-fold ( p .001), and 4-fold ( p .004), respectively, compared with IMA. Furthermore, the cav-1:eNOS immunostaining ratio in the media correlated with intimal thickening (r 2 = 0.5). Our results suggest a close relationship between increased cav-1 and diseased blood vessels.
Publisher: Wiley
Date: 25-02-2013
DOI: 10.1111/NEP.12028
Abstract: Preterm birth (birth prior to 37 completed weeks of gestation) may occur at a time when the infant kidney is very immature and nephrogenesis is often ongoing. In autopsied preterm human kidneys and in a baboon model of preterm birth it has been shown that nephrogenesis continues after preterm birth, with a significant increase in the number of glomerular generations and number of nephrons formed within the kidney after birth. Of concern, however, morphologically abnormal glomeruli (with a cystic Bowman's space) are often observed the abnormal glomeruli are only located in the outer renal cortex, suggesting that it is the recently formed glomeruli (perhaps those formed in the extra-uterine environment) that are affected. The proportion of abnormal glomeruli within the renal cortex differs between infants with some kidneys appearing normal whereas others are severely affected. This suggests that it may be haemodynamic factors and/or factors in the neonatal care of the infant that lead to the glomerular abnormalities. Indeed, the haemodynamic transition at birth where there is a marked increase in systemic blood pressure and renal blood flow are likely to lead to injury of glomerular capillaries, although further studies are required to elucidate this. In order to optimize renal health at the beginning of life in the preterm infant, it is imperative in future studies to gain an understanding of the causes of the glomerular abnormalities in the preterm neonate.
Publisher: Springer Science and Business Media LLC
Date: 08-2016
Abstract: Preterm births account for approximately 10% of births worldwide, with the majority (∼80%) being moderate preterm. Our aim was to determine the effects of moderate preterm birth on survival and long-term growth of male and female offspring using an ovine model of preterm birth that was preceded by a clinically relevant dose of corticosteroids. Ewes were induced to deliver preterm or at term those assigned to deliver preterm were administered antenatal betamethasone (11.4 mg, 2 doses, 24 hours apart). The growth (body weight and body dimensions) of offspring was monitored to adulthood (62 weeks) when the animals were humanely killed for organ collection. Survival in the immediate period following preterm birth was high (75% for both sexes). However, there were unexpected deaths between 5 and 12 weeks of age, as a result of vitamin E/selenium deficiency this only occurred in preterm offspring. From birth until adolescence, preterm lambs were lighter than term lambs (controls). After this time, there was gradual catch-up in body weight in preterm females, whereas in preterm males, body weight remained lower than in controls. Preterm sheep were smaller in stature than controls throughout life. This clinically relevant model of preterm birth leads to equally high survival rates in both sexes and is an excellent animal model in which to examine the effects of moderate preterm birth on growth and development of organ systems into adulthood.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2007
DOI: 10.1007/S00467-007-0572-5
Abstract: A reduced nephron complement at birth renders the kidney susceptible to renal disease in adulthood. Retinoic acid (RA the active metabolite of vitamin A) is linked to nephrogenesis in vitro and in vivo. The aim of this study was to determine the effect of administration of retinoic acid in midgestation in rats on nephron endowment in offspring exposed to maternal protein restriction. Rats were fed either a normal-protein diet (NPD) or a low-protein diet (LPD) during pregnancy and lactation. Half of the dams in the LPD group were injected intraperitoneally with retinoic acid (20 mg/kg) during gestation at embryonic day 11.5. At 4 weeks of age, the offspring were anesthetized and perfusion-fixed, and nephron number estimated using unbiased stereological techniques. Body weight and kidney volume was significantly reduced in all LPD offspring. There was a significant 29% reduction in nephron number in the LPD group compared with the NPD offspring, whereas the number of nephrons in kidneys from the LPD + RA offspring was not significantly different compared with controls. In conclusion, administration of a single bolus dose of retinoic acid during midgestation restored nephron endowment to normal in offspring exposed to maternal protein restriction.
Publisher: American Physiological Society
Date: 15-05-2013
DOI: 10.1152/AJPRENAL.00172.2012
Abstract: Preterm neonates are born while nephrogenesis is ongoing and are commonly exposed to factors in the extrauterine environment that may impair renal development. Supplemental oxygen therapy exposes the preterm infant to a hyperoxic environment that may induce oxidative stress. Our aim was to determine the immediate and long-term effects of exposure to hyperoxia, during the period of postnatal nephrogenesis, on renal development. Newborn mice (C57BL/6J) were kept in a normoxic (room air, 21% oxygen) or a controlled hyperoxic (65% oxygen) environment from birth to postnatal day 7 ( P7d). From P7d, animals were maintained in room air until early adulthood at postnatal day 56 ( P56d) or middle age (10 mo P10mo). Pups were assessed for glomerular maturity and renal corpuscle cross-sectional area at P7d (control n = 14 hyperoxic n = 14). Nephron number and renal corpuscle size were determined stereologically at P56d (control n = 14 hyperoxic n = 14) and P10mo (control n = 10 hyperoxic n = 10). At P7d, there was no effect of hyperoxia on glomerular size or maturity. In early adulthood ( P56d), body weights, relative kidney weights and volumes, and nephron number were not different between groups, but the renal corpuscles were significantly enlarged. This was no longer evident at P10mo, with relative kidney weights and volumes, nephron number, and renal corpuscle size not different between groups. Furthermore, hyperoxia exposure did not significantly accelerate glomerulosclerosis in middle age. Hence, our findings show no overt long-term deleterious effects of early life hyperoxia on glomerular structure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2003
DOI: 10.1161/01.ATV.0000080686.39871.54
Abstract: Objective— High plasma cholesterol or homocysteine is a risk factor for atherosclerosis. Cholesterol and methionine, the precursor of homocysteine, are rarely eaten separately. Thus, the aims of this study were to determine neointima formation, aortic reactivity, and factors involved in endothelial function in rabbits fed high dietary cholesterol, methionine, or a combination of the two for 12 weeks. Methods and Results— Rabbit dietary groups were randomized into the following: control (Con), 0.5% cholesterol (Chol), 1% methionine (Meth), and 1% methionine+0.5% cholesterol (MethChol). Aortic reactivity was studied by isometric tension techniques, aortic volumetric analysis was determined by stereological techniques, and immunohistochemistry was used to localize endothelial and inducible NO synthases, superoxide dismutase, macrophages, and nitrotyrosine. Atherosclerosis was present in the Chol and MethChol groups. Endothelium-dependent relaxation was virtually abolished in the MethChol group compared with control. Such decrease in relaxation was not attributable to a vascular smooth muscle cell defect or to a decrease in endothelial NO synthase or superoxide dismutase content. Macrophages and inducible NO synthase immunoreactivity were present in Chol and MetChol groups. Conclusions— The combination of high dietary cholesterol plus methionine virtually abolishes endothelium-dependent relaxation, underscoring the importance of multiple risk factors in the development of cardiovascular disease.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.CARPATH.2009.07.003
Abstract: Diabetes in human subjects is often associated with hypertension. The aim of this study was to examine the development of cardiac fibrosis following induction of type 1 diabetes in genetically hypertensive rats. Diabetes was induced by streptozotocin (STZ) injection in 8-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) for a duration of 16 or 24 weeks. Aged-matched, nondiabetic WKY and SHRs were used as controls. At termination of treatment, the rats were anaesthetized, hearts arrested in diastole and perfusion fixed. A comprehensive examination of cardiac fibrosis throughout the right and left ventricles was undertaken in picrosirius red-stained sections, using image analysis and by undertaking collagen type I and type III immunohistochemistry. Induction of diabetes in the SHRs led to a marked increase in the levels of interstitial fibrosis in the left ventricle plus septum (LV+S) at both 16 and 24 weeks duration (59% and 43% increase, respectively) and also in the right ventricle after 24 weeks duration of diabetes (35% increase compared to the nondiabetic SHR). Exacerbated perivascular fibrosis was also observed in the LV+S in the diabetic-hypertensive rats at the later time point. These effects of induction of diabetes were not observed in the normotensive strain. Our findings clearly demonstrate elevations in cardiac fibrosis when type 1 diabetes is combined with hypertension. Our findings thus stress the importance of closely monitoring both blood pressure and glucose levels in type 1 diabetic patients in order to prevent myocardial collagen deposition.
Publisher: Wiley
Date: 07-1996
DOI: 10.1111/J.1440-1681.1996.TB02794.X
Abstract: 1. The effect of high and low dose angiotensin converting enzyme (ACE) inhibition and the contribution of bradykinin potentiation in this treatment on left and right ventricle weights and wall volume was investigated in immature spontaneously hypertensive rats (SHR). 2. Male SHR were treated from 7 to 11 weeks of age with perindopril (an ACE inhibitor) at a low dose of 0.1 mg/kg per day or a high dose of 1 mg/kg per day. Half the animals were also treated with a bradykinin receptor antagonist, HOE 140 (500 μg/kg per day). 3. After 4 weeks of treatment, hearts were arrested in diastole and perfusion fixed. The right and left ventricle plus septum were weighed, cut into 1 mm slices and volume was determined using the Cavalieri principle. 4. Low dose perindopril treatment did not significantly affect blood pressure in the SHR. High dose perindopril treatment maintained blood pressure at a level similar to Wistar‐Kyoto (WKY) rats. 5. Growth of the right ventricle was not influenced by ACE inhibition. However, high dose treatment significantly lowered the left ventricle plus septum volume: bodyweight ratio (LV + S VOL:BWT) compared with control SHR (2.85 ± 0.02 vs 3.36 ± 0.08 mm 3 /g, respectively) to a level similar to the normotensive WKY rats (2.80 ± 0.11 mm 3 /g). Similarly, low dose treatment significantly lowered the LV + S VOL:BWT ratio (2.89 ± 0.09 mm 3 /g). HOE 140 treatment did not reverse the effect of ACE inhibition. Similar effects were observed on left ventricular weights. 6. ACE inhibition, independent of its blood pressure lowering effect, prevents the development of left ventricular hypertrophy in the SHR but does not influence growth of the right ventricle. This effect of ACE inhibition does not appear to be mediated by bradykinin potentiation.
Publisher: Wiley
Date: 24-10-2008
DOI: 10.1002/AR.20789
Abstract: In most species including man, cardiomyocytes cease proliferating soon after birth when they become terminally differentiated. A reduced complement of cardiomyocytes in infancy may adversely impact on the function and adaptive capabilities of the heart in later life. Low birthweight is associated with an increased risk of heart disease in adults, but little is known about its effect on the number of cardiomyocytes. Using naturally occurring differences in birthweight, our aim was to determine the effect of birthweight on cardiomyocyte number in postnatal lambs. At 9 weeks after term birth, when the final number of cardiomyocytes is considered to be established, hearts were collected at necropsy from seven singleton and seven twin lambs. Hearts were perfusion-fixed, and tissue s les were systematically taken from the left ventricle plus intraventricular septum (LV+S) and the right ventricle (RV). The number of cardiomyocyte nuclei was estimated using an unbiased optical disector-fractionator stereological technique, and the total number of cardiomyocytes was determined. Weights of the total heart, LV+S and RV were significantly related to both birthweight and necropsy weight. In the LV+S but not the RV, cardiomyocyte number was significantly and directly related to heart tissue weight, birthweight, and necropsy weight. We conclude that the final number of cardiomyocytes in the LV+S is related to prenatal and early postnatal growth, and is proportionate to the weight of heart tissue. A low cardiomyocyte number in the LV+S following restricted fetal growth may contribute to the increased incidence of heart disease in adults born with low birthweight. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: American Physiological Society
Date: 15-07-2014
DOI: 10.1152/AJPRENAL.00439.2013
Abstract: Worldwide, approximately 10% of neonates are born preterm. The majority of preterm neonates are born when the kidneys are still developing therefore, during the early postnatal period renal function is likely reflective of renal immaturity and/or injury. This study evaluated glomerular and tubular function and urinary neutrophil gelatinase-associated lipocalin (NGAL a marker of renal injury) in preterm neonates during the first month of life. Preterm and term infants were recruited from Monash Newborn (neonatal intensive care unit at Monash Medical Centre) and Jesse McPherson Private Hospital, respectively. Infants were grouped according to gestational age at birth: ≤28 wk ( n = 33), 29–31 wk ( n = 44), 32–36 wk ( n = 32), and term (≥37 wk ( n = 22)). Measures of glomerular and tubular function were assessed on postnatal days 3–7, 14, 21, and 28. Glomerular and tubular function was significantly affected by gestational age at birth, as well as by postnatal age. By postnatal day 28, creatinine clearance remained significantly lower among preterm neonates compared with term infants however, sodium excretion was not significantly different. Pathological proteinuria and high urinary NGAL levels were observed in a number of neonates, which may be indicative of renal injury however, there was no correlation between the two markers. Findings suggest that neonatal renal function is predominantly influenced by renal maturity, and there was high capacity for postnatal tubular maturation among preterm neonates. There is insufficient evidence to suggest that urinary NGAL is a useful marker of renal injury in the preterm neonate.
Publisher: Public Library of Science (PLoS)
Date: 26-11-2012
Publisher: SAGE Publications
Date: 02-2006
Abstract: Evidence suggests that angiotensin type 2 receptor (AT 2 R) and angiotensin-converting enzyme 2 (ACE2) play a protective role in atherogenesis. These factors have not been identified in rabbit atherosclerotic plaques. Our goal was to localize ACE2 and AT 2 R in rabbit atherosclerotic tissues, and determine which cell types express these factors. New Zealand White rabbits were fed either a control diet or a 0.5% cholesterol diet ( n=8/group) for 12 weeks. Paraffin-fixed thoracic aorta were serially sectioned and processed for immunohistochemistry using commercially available antibodies to ACE2, AT 2 R, RAM 11 (to identify macrophages), and α smooth muscle cell actin (αSMC) to identify smooth muscle cells and myofibroblasts. AT 2 R immunoreactivity, but not ACE2 immunoreactivity, was clearly present in endothelia overlying normal wall. However, both AT 2 R and ACE2 immunoreactivity were clearly present in endothelia overlying neo-intima formation and atherosclerotic plaques. Within plaques, both AT 2 R and ACE2 immunoreactivity were observed in macrophages and αSMC actin-positive cells. Examination of serial sections showed that the majority of cells were both ACE2- and AT 2 R-positive. Macrophages and αSMC actin-positive cells produce ACE2 and the AT 2 R in atherosclerotic plaques. Determining a role for these factors in the control of atherosclerosis will require additional studies.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.YJMCC.2004.08.004
Abstract: Ang II acting at AT(1)Rs has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, effects which are believed to be opposed by AT(2)R stimulation. AT(1) and AT(2)R expression are up regulated in senescent hearts, and other components of the local renin-angiotensin system are also dramatically increased in the ageing heart. Therefore, the aim of this study was to determine the role of the AT(2)R in aged rats by determining their potential contribution to the chronic antihypertensive and cardiovascular effects of AT(1)R blockade. Radiotelemetry probes were implanted into senescent (20 months) male Wistar-Kyoto (WKY) rats, and baseline recordings of mean arterial pressure (MAP) were made for 1 week. Candesartan cilexetil (2 mg/kg per day) was given in drinking water, while an additional group simultaneously received the AT(2)R antagonist, PD123319 (10 mg/kg per day) via osmotic mini-pump. At the end of the 4 weeks treatment period, animals were perfusion-fixed to enable histological analysis of cardiovascular structure. MAP was decreased by candesartan cilexetil, however, this effect was not further influenced by PD123319. Cardiac hypertrophy and fibrosis, and aortic hypertrophy were all significantly reduced by candesartan cilexetil. Most interestingly, these structural changes were reversed by concomitant PD123319 administration, despite the lack of AT(2)R-mediated effects on MAP. These results suggest that the AT(2)R does not exert a significant influence on chronic blood pressure regulation in senescent rats. However, PD123319 did reverse AT(1)R-mediated regression of cardiovascular hypertrophy and fibrosis, highlighting the important role of the AT(2)R on cardiovascular structure in the ageing heart and vasculature.
Publisher: Wiley
Date: 2003
DOI: 10.1046/J.1440-1681.2003.03793.X
Abstract: 1. Angiotensin‐converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B 2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High‐ and low‐perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low‐dose perindopril were still considered hypertensive. Neither low‐dose nor high‐dose perindopril treatment had any observable effect on glomerular number (23 876 ± 1201 vs 26 240 ± 1465 glomeruli/kidney, respectively) or volume (2.25 ± 0.21 and 1.96 ± 0.06 × 10 −3 mm 3 , respectively) compared with controls (glomerular number 25 866 ± 1210 glomeruli/kidney glomerular volume 2.24 ± 0.21 × 10 −3 mm 3 ). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 ± 550.9, 8699.7 ± 427.6, 9081.9 ± 453.6, 8830.2 ± 521.2 and 8559.4 ± 341.4 mm 2 for SHR, SHR low‐dose perindopril, SHR low‐dose perindopril + B 2 antagonist, SHR high‐dose perindopril and SHR high‐dose perindopril + B 2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high‐dose nor low‐dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.IJCARD.2012.03.075
Abstract: Myocardial microvascular dysfunction has been implicated in the pathogenesis of myocardial infarction (MI). We tested the hypothesis that patients with MI have lower microvasculature density in myocardium remote from the site of infarction than patients with similar extent of coronary artery disease (CAD) without MI and examined the relationship between myocardial capillary length density and plasma levels of angiogenesis-related biomarkers. We analyzed biopsies from non-ischemic left ventricular (LV) myocardium and measured plasma levels of angiogenesis-related biomarkers in patients undergoing coronary artery bypass graft surgery, 57 without previous MI (no-MI) and 27 with recent non-ST-segment-elevation MI (NSTEMI). Comparison was made with biopsies from 31 aortic stenosis (AS) patients and 6 patients with "normal" LV without CAD. Myocardial microvascular density of NSTEMI patients was approximately half the density of no-MI patients, and similar to AS patients. Whereas the reduced microvascular density of AS patients was accounted for by their cardiomyocyte hypertrophy, this was not the case for NSTEMI patients, who had higher diffusion radius/cardiomyocyte width ratio than no-MI, "normal" LV, and AS patients. NSTEMI patients had lower plasma levels of carboxymethyl lysine and low molecular weight fluorophores, higher vascular endothelial growth factor (VEGF) receptor-1/VEGF-A ratio, and higher endostatin and hepatocyte growth factor levels than no-MI patients. Recent MI was associated with reduced microvasculature density in myocardium remote from the site of infarction and alteration in plasma levels of angiogenesis-related biomarkers.
Publisher: MDPI AG
Date: 29-12-2015
DOI: 10.3390/NU7010119
Publisher: Springer Science and Business Media LLC
Date: 10-01-2010
DOI: 10.1007/S00125-009-1645-8
Abstract: We measured components of the kallikrein- kinin system in human type 2 diabetes mellitus and the effects of statin therapy on the circulating kallikrein-kinin system. Circulating levels of bradykinin and kallidin peptides, and high and low molecular weight kininogens, as well as plasma and tissue kallikrein, and kallistatin were measured in non-diabetic and diabetic patients before coronary artery bypass graft surgery. Tissue kallikrein levels in atrial tissue were examined by immunohistochemistry and atrial tissue kallikrein mRNA quantified. Plasma levels of tissue kallikrein were approximately 62% higher in diabetic than in non-diabetic patients (p=0.001), whereas no differences were seen in circulating levels of bradykinin and kallidin peptides, and high and low molecular weight kininogens, or in plasma kallikrein or kallistatin. Immunohistochemistry revealed a twofold increase in tissue kallikrein levels in atrial myocytes (p= 0.015), while tissue kallikrein mRNA levels were increased eightfold in atrial tissue of diabetic patients (p=0.014). Statin therapy did not change any variables of the circulating kallikrein-kinin system. Neither aspirin, calcium antagonists, beta blockers or long-acting nitrate therapies influenced any kallikrein-kinin system variable. Tissue kallikrein levels are increased in type 2 diabetes, whereas statin therapy does not modify the circulating kallikrein-kinin system. Cardiac tissue kallikrein may play a greater cardioprotective role in type 2 diabetic than in non-diabetic patients and contribute to the benefits of ACE inhibitor therapy in type 2 diabetic patients. However, our findings do not support a role for the kallikrein-kinin system in mediating the effects of statin therapy on endothelial function.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
DOI: 10.1161/HYPERTENSIONAHA.110.165043
Abstract: Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mortality than similarly aged men, despite less obstructive coronary artery disease. To determine whether the myocardial structure and coronary microvasculature of women differs from that of men, we performed histological analysis of biopsies from nonischemic left ventricular myocardium from 46 men and 11 women undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation, or furosemide therapy. The 2 patient groups had similar clinical characteristics, apart from a lower body surface area (BSA) in women ( P =0.0015). Women had less interstitial fibrosis than men ( P =0.019) but similar perivascular fibrosis. Arteriolar wall area/circumference ratio, a measure of arteriolar wall thickness, was 47% greater in women than men ( P =0.012). Cardiomyocyte width and diffusion radius were positively correlated, and capillary length density was negatively correlated with BSA ( P .05). Whereas cardiomyocyte width, capillary length density, diffusion radius, and cardiomyocyte width/BSA ratio were similar for men and women, women had a greater diffusion radius/BSA ratio ( P =0.0038) and a greater diffusion radius/cardiomyocyte width ratio ( P =0.027). Women also had lower vascular endothelial growth factor (VEGF) receptor-1 levels ( P =0.048) and VEGF receptor-1/VEGF-A ratio ( P =0.024) in plasma. We conclude that women with extensive coronary artery disease have greater arteriolar wall thickness and diffusion radius relative to BSA and to cardiomyocyte width than men, which may predispose to myocardial ischemia. Additional studies of larger numbers of women with less extensive coronary artery disease are required to confirm these findings.
Publisher: Public Library of Science (PLoS)
Date: 25-07-2013
Publisher: Wiley
Date: 20-10-2020
DOI: 10.1002/AR.24516
Abstract: Diffusion tensor imaging (DTI) is an MRI technique that can be used to map cardiomyocyte tracts and estimate local cardiomyocyte and sheetlet orientation within the heart. DTI measures diffusion distances of water molecules within the myocardium, where water diffusion generally occurs more freely along the long axis of cardiomyocytes and within the extracellular matrix, but is restricted by cell membranes such that transverse diffusion is limited. DTI can be undertaken in fixed hearts and it allows the three-dimensional mapping of the cardiac microarchitecture, including cardiomyocyte organization, within the whole heart. The objective of this study was to use DTI to compare the cardiac microarchitecture and cardiomyocyte organization in archived fixed left ventricles of lambs that were born either preterm (n = 5) or at term (n = 7), at a postnatal timepoint equivalent to about 6 years of age in children. Although the findings support the feasibility of retrospective DTI scanning of fixed hearts, several hearts were excluded from DTI analysis because of poor scan quality, such as ghosting artifacts. The preliminary findings from viable DTI scans (n = 3/group) suggest that the extracellular compartment is altered and that there is an immature microstructural phenotype early in postnatal life in the LV of lambs born preterm. Our findings support a potential time-efficient imaging role for DTI in detecting abnormal changes in the microstructure of fixed hearts of former-preterm neonates, although further investigation into factors that affect scan quality is required.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/SREP23756
Abstract: Quantitative assessment of myocardial development and disease requires accurate measurement of cardiomyocyte volume, nuclearity (nuclei per cell), and ploidy (genome copies per cell). Current methods require enzymatically isolating cells, which excludes the use of archived tissue, or serial sectioning. We describe a method of analysis that permits the direct simultaneous measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections. To demonstrate the utility of our technique, heart tissue was obtained from four species (rat, mouse, rabbit, sheep) at up to three life stages: prenatal, weaning and adulthood. Thick (40 μm) paraffin sections were stained with Wheat Germ Agglutinin-Alexa Fluor 488 to visualise cell membranes, and DAPI (4′,6-diamidino-2-phenylindole) to visualise nuclei and measure ploidy. Previous methods have been restricted to thin sections (2–10 μm) and offer an incomplete picture of cardiomyocytes. Using confocal microscopy and three-dimensional image analysis software (Imaris Version 8.2, Bitplane AG, Switzerland), cardiomyocyte volume, nuclearity, and ploidy were measured. This method of staining and analysis of cardiomyocytes enables accurate morphometric measurements in thick histological sections, thus unlocking the potential of archived tissue. Our novel time-efficient method permits the entire cardiomyocyte to be visualised directly in 3D, eliminating the need for precise alignment of serial sections.
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.
Publisher: Public Library of Science (PLoS)
Date: 29-11-2013
Publisher: Elsevier
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 04-2011
Abstract: Although the majority of preterm neonates now survive infancy, there is emerging epidemiological evidence to demonstrate that in iduals born preterm exhibit an elevated risk for the development of hypertension and renal impairment later in life, thus supporting the developmental origins of health and disease hypothesis. The increased risk may potentially be attributed to a negative impact of preterm birth on nephron endowment. Indeed, at the time when most preterm neonates are delivered, nephrogenesis in the kidney is still ongoing with the majority of nephrons normally formed during the third trimester of pregnancy. A number of clinical studies have provided evidence of altered renal function during the neonatal period, but to date there have been limited studies describing the consequences of preterm birth on kidney structure. Importantly, studies in the preterm baboon have shown that nephrogenesis is clearly ongoing following preterm birth however, the presence of abnormal glomeruli (up to 18% in some cases) is of concern. Similar glomerular abnormalities have been described in autopsied preterm infants. Prenatal and postnatal factors such as exposure to certain medications, hyperoxia and intrauterine and/or extrauterine growth restriction are likely to have a significant influence on nephrogenesis and final nephron endowment. Further studies are required to determine the factors contributing to renal maldevelopment and to identify potential interventional strategies to maximize nephron endowment at the start of life, thereby optimizing long-term renal health for preterm in iduals.
Publisher: Cambridge University Press (CUP)
Date: 15-05-2017
DOI: 10.1017/S2040174417000381
Abstract: Low birth weight is associated with increased risk of cardiovascular disease in adulthood. Intrauterine growth restriction (IUGR) hearts have fewer CMs in early postnatal life, which may impair postnatal cardiovascular function and hence, explain increased disease risk, but whether the cardiomyocyte deficit persists to adult life is unknown. We therefore studied the effects of experimentally induced placental restriction (PR) on cardiac outcomes in young adult sheep. Heart size, cardiomyocyte number, nuclearity and size were measured in control ( n =5) and PR ( n =5) male sheep at 1 year of age. PR lambs were 36% lighter at birth ( P =0.007), had 38% faster neonatal relative growth rates ( P =0.001) and had 21% lighter heart weights relative to body weight as adults ( P =0.024) than control lambs. Cardiomyocyte number, nuclearity and size in the left ventricle did not differ between control and PR adults hearts of both groups contained cardiomyocytes (CM) with between one and four nuclei. Overall, cardiomyocyte number in the adult left ventricle correlated positively with birth weight but not with adult weight. This study is the first to demonstrate that intrauterine growth directly influences the complement of CM in the adult heart. Cardiomyocyte size was not correlated with cardiomyocyte number or birth weight. Our results suggest that body weight at birth affects lifelong cardiac functional reserve. We hypothesise that decreased cardiomyocyte number of low birth weight in iduals may impair their capacity to adapt to additional challenges such as obesity and ageing.
Publisher: Cambridge University Press (CUP)
Date: 30-04-2012
DOI: 10.1017/S2040174412000244
Abstract: Alcohol consumption during pregnancy remains common in many countries. Exposure to even low amounts of alcohol (i.e. ethanol) in pregnancy can lead to the heterogeneous fetal alcohol spectrum disorders (FASD), while heavy alcohol consumption can result in the fetal alcohol syndrome (FAS). FAS is characterized by cerebral dysfunction, growth restriction and craniofacial malformations. However, the effects of lower doses of alcohol during pregnancy, such as those that lead to FASD, are less well understood. In this article, we discuss the findings of recent studies performed in our laboratories on the effects of fetal alcohol exposure using sheep, in which we investigated the effects of late gestational alcohol exposure on the developing brain, arteries, kidneys, heart and lungs. Our studies indicate that alcohol exposure in late gestation can (1) affect cerebral white matter development and increase the risk of hemorrhage in the fetal brain, (2) cause left ventricular hypertrophy with evidence of altered cardiomyocyte maturation, (3) lead to a decrease in nephron number in the kidney, (4) cause altered arterial wall stiffness and endothelial and smooth muscle function and (5) result in altered surfactant protein mRNA expression, surfactant phospholipid composition and pro-inflammatory cytokine mRNA expression in the lung. These findings suggest that fetal alcohol exposure in late gestation can affect multiple organs, potentially increasing the risk of disease and organ dysfunction in later life.
Publisher: Wiley
Date: 16-03-2023
DOI: 10.1002/AR.25202
Abstract: Postnatal corticosteroids are used in the critical care of preterm infants for the prevention and treatment of bronchopulmonary dysplasia. We aimed to investigate the effects of early postnatal dexamethasone therapy and dose on cardiac maturation and morphology in preterm lambs. Lambs were delivered prematurely at ~128 days of gestational age and managed postnatally according to best clinical practice. Preterm lambs were administered dexamethasone daily at either a low‐dose ( n = 9) or a high‐dose ( n = 7), or were naïve to steroid treatment and administered saline ( n = 9), over a 7‐day time‐course. Hearts were studied at postnatal Day 7 for gene expression and assessment of myocardial structure. High‐dose dexamethasone treatment in the early postnatal period led to marked differences in cardiac gene expression, altered cardiomyocyte maturation and reduced cardiomyocyte endowment in the right ventricle, as well as increased inflammatory infiltrates into the left ventricle. Low‐dose exposure had minimal effects on the preterm heart. Neonatal dexamethasone treatment led to adverse effects in the preterm heart in a dose‐dependent manner within the first week of life. The observed cardiac changes associated with high‐dose postnatal dexamethasone treatment may influence postnatal growth and remodeling of the preterm heart and subsequent long‐term cardiac function.
Publisher: Wiley
Date: 20-03-2013
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/136942
Abstract: Epidemiological studies have clearly demonstrated a strong association between low birth weight and long-term renal disease. A potential mediator of this long-term risk is a reduction in nephron endowment in the low birth weight infant at the beginning of life. Importantly, nephrons are only formed early in life during normal gestation, nephrogenesis is complete by about 32–36 weeks, with no new nephrons formed after this time during the lifetime of the in idual. Hence, given that a loss of a critical number of nephrons is the hallmark of renal disease, an increased severity and acceleration of renal disease is likely when the number of nephrons is already reduced prior to disease onset. Low birth weight can result from intrauterine growth restriction (IUGR) or preterm birth a high proportion of babies born prematurely also exhibit IUGR. In this paper, we describe how IUGR and preterm birth adversely impact on nephrogenesis and how a subsequent reduced nephron endowment at the beginning of life may lead to long-term risk of renal disease, but not necessarily hypertension.
Publisher: Springer Science and Business Media LLC
Date: 02-2010
Abstract: The aim of this study was to determine the effect of vitamin D deficiency from conception until 4 weeks of age on the development of the heart in rat offspring. Sprague-Dawley (SD) rats were fed either a vitamin D deplete or vitamin D-replete diet for 6 weeks prior to pregnancy, during pregnancy and throughout lactation. Cardiomyocyte number was determined in fixed hearts of offspring at postnatal day 3 and 4 weeks of age using an optical disector/fractionator stereological technique. In other litters, cardiomyocytes were isolated from freshly excised hearts to determine the proportion of mononucleated and binucleated cardiomyocytes. Maternal vitamin D deficiency had no effect on cardiomyocyte number, cardiomyocyte area, or the proportion of mononucleated/binucleated cardiomyocytes in 3-day-old male and female offspring. Importantly, however, vitamin D deficiency led to an increase in left ventricle (LV) volume that was accompanied by an increase in cardiomyocyte number and size, and in the proportion of mononucleated cardiomyocytes at 4 weeks of age. Our findings suggest that exposure to vitamin D deficiency in utero and early life leads to delayed maturation and subsequent enhanced growth (proliferation and hypertrophy) of cardiomyocytes in the LV. This may lead to altered cardiac function later in life.
Publisher: American Physiological Society
Date: 09-2007
DOI: 10.1152/AJPREGU.00119.2007
Abstract: Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about the importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesized that induction of IUGR during late gestation alters the RAS, and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on 1) nephron number 2) mRNA expression of angiotensin AT 1 and AT 2 receptors, angiotensinogen, and renin genes in the kidney and 3) the size of maculae densae. IUGR was induced in fetal sheep ( n = 7) by umbilical-placental embolization from 110 to 130 days of the ∼147-day gestation saline-infused fetuses served as controls ( n = 7). S les of cortex from the left kidney were frozen, and the right kidney was perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume, and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT 1 and AT 2 receptors, angiotensinogen, and renin in the renal cortex was determined. In IUGR fetuses at 130 days, body and kidney weights were significantly reduced and nephron number was reduced by 24%. There was no difference in renin, angiotensinogen, or AT 1 and AT 2 receptor mRNA expression levels in the IUGR kidneys compared with controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment but does not affect renal corpuscle or macula densa size, or renal RAS gene expression.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000327073
Abstract: At the time when most preterm babies are delivered, nephrogenesis is still ongoing, with the majority of nephrons normally formed during the third trimester of pregnancy. The extrauterine environment, however, is suboptimal for organogenesis, and therefore renal development is likely to be adversely affected by preterm birth. In the long-term, there is emerging evidence of high blood pressure and renal dysfunction amongst young adults born preterm. There is little knowledge to date, however, regarding the effects of preterm birth on renal structural development, perhaps due to the lack of an appropriate animal model. We have demonstrated that the baboon ( i Papio /i sp.) has a similar time course of nephrogenesis as the human kidney, and the baboon neonate can also be cared for in the same manner as a human neonate following preterm birth. Through a series of studies assessing renal development in the baboon model of preterm birth, involving the use of gold-standard stereological techniques, we have demonstrated that nephron endowment in the preterm baboon kidney is not reduced. Furthermore, antenatal glucocorticoid exposure prior to preterm delivery was associated with an increase in mature nephrons. There was, however, evidence of morphological abnormalities in a variable percentage of the glomeruli formed ex utero i . /i Further research is therefore essential in order to establish what factors are involved in contributing to the glomerular abnormalities, and to identify ways in which ‘normal’ renal development can be conserved and optimised in the extrauterine setting.
Publisher: Wiley
Date: 20-01-2010
DOI: 10.1002/AR.21084
Abstract: Maternal protein restriction leads to a reduction in the number of cardiomyocytes in the rat heart at birth. However, in rats, cardiomyocytes continue to proliferate until about 2 weeks after birth. Hence, this study aimed to examine the effect of maternal protein restriction, on the number of cardiomyocytes in the young rat heart at a time point when the cardiomyocytes have ceased proliferating and are terminally differentiated. Female Wistar Kyoto rats were fed either a normal protein diet (NPD 20% casein) or a low protein diet (LPD 8.7% casein) during pregnancy and lactation. Offspring (seven males and seven females per group) were perfusion fixed at 4 weeks of age. Heart volume and total cardiomyocyte number were determined using stereological techniques. At 4 weeks of age, body weights in both male and female LPD offspring were significantly reduced compared with NPD controls whereas relative heart volumes were significantly increased in LPD offspring. Total number of cardiomyocytes was not significantly different between groups. In both groups, there was a significant linear correlation between cardiomyocyte number and heart volume. In conclusion, total cardiomyocyte number in the postproliferative rat heart does not appear to be affected by maternal protein restriction per se but is directly related to heart size.
Publisher: Springer Science and Business Media LLC
Date: 12-2002
DOI: 10.1007/S00467-002-0998-8
Abstract: This study investigated the effects of a high-protein diet during pregnancy on nephron endowment and subsequent levels of blood pressure in the offspring. Female WKY rats were fed either a normal (20%, NPD) or a high (54%, HPD) protein diet during pregnancy. Male offspring were paired at birth. At 4 weeks of age, 1 of the pair was randomly chosen for perfusion fixation, and total glomerular number, and thereby nephron number, was estimated using an unbiased stereological technique. The other rat of the pair was allowed to grow to 30 weeks of age, during which time tail cuff systolic blood pressure was monitored twice weekly. There was no effect of the HPD on birth weight (NPD 4.23+/-0.53 g, HPD 4.26+/-0.45 g, mean+/-SD), kidney weight (NPD 0.372+/-0.049 g, HPD 0.337+/-0.090 g), or total nephron number (NPD 27,191+/-3,512, HPD 26,738+/-4,735). Systolic blood pressure at 30 weeks was 170+/-14 mmHg in NPD and 169+/-14 in HPD offspring. These findings show that a HPD during pregnancy did not lead to an increase in birth weight, kidney weight, or nephron endowment, nor did the HPD affect adult blood pressure.
Publisher: Springer Science and Business Media LLC
Date: 13-08-2015
DOI: 10.1007/S00394-014-0752-6
Abstract: Epidemiological and experimental studies demonstrate that intrauterine growth restriction (IUGR) followed by accelerated postnatal growth leads to increased risk of developing cardiac disease in adulthood. The aim of this study was to examine the effect of early life growth restriction on cardiac structure and function in young adult rats. IUGR was induced in Wistar Kyoto dams through administration of a low protein diet (LPD 8.7% casein) during pregnancy and lactation controls received a normal protein diet (NPD 20% casein). Cardiac function and structure were assessed in female NPD (n = 7) and LPD (n = 7) offspring at 18 weeks of age by echocardiography and pressure-volume techniques, and systolic blood pressure by tail-cuff sphygmomanometry. LPD offspring remained significantly smaller throughout life compared to controls. There were no differences in the levels of systolic blood pressure, left ventricular cardiac dimensions, heart rate, ejection fraction and fractional shortening of the cardiac muscle between the investigated groups. Aortic peak systolic velocity was significantly reduced in the LPD group (P = 0.02). Our findings support the idea that the programming of adult cardiovascular disease can be prevented or delayed in IUGR offspring when postnatal growth trajectory resembles that of in utero.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2005
DOI: 10.1161/01.HYP.0000193504.51489.CF
Abstract: Angiotensin II (Ang II) has important actions on the heart via type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The link between AT 1 receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT 2 receptor, which reportedly antagonizes the AT 1 receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT 2 receptor and its modulation of the AT 1 receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT 1 and AT 2 to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT 1 /AT 2 stoichiometry on cardiomyocyte hypertrophy. In myocytes expressing only the AT 1 receptor, Ang II stimulation promoted robust hypertrophy (increased protein:DNA ratio and phenotypic changes) via activation of mitogen-activated protein kinases (MAPKs). Titration of the AT 2 receptor against the AT 1 receptor did not inhibit Ang II–mediated cardiomyocyte hypertrophy. Instead, basal and Ang II–mediated hypertrophy was increased in line with the lified expression of the AT 2 receptor, indicating a capacity for the AT 2 receptor to enhance basal cardiomyocyte growth. Indeed, expression of the AT 2 receptor alone resulted in hypertrophy remarkably, this was unaffected by Ang II stimulation or the AT 2 receptor–specific ligands PD123319 and CGP42112. Although previous studies have indicated that the AT 2 receptor can antagonize MAPK activation via the AT 1 receptor, we found no evidence for this in cardiomyocytes. Thus, the AT 2 receptor promotes ligand-independent, constitutive cardiomyocyte hypertrophy and does not directly antagonize the AT 1 receptor in this setting.
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1440-1681.1997.TB01221.X
Abstract: 1. In the present study the role of angiotensin II (AngII) in the development of cardiac hypertrophy in diabetes combined with hypertension was investigated. 2. Diabetes was induced in 8-week-old male spontaneously hypertensive rats (SHR) by intravenous injection of streptozotocin (45 mg/kg bodyweight). Diabetic SHR were treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril at a dose of 0.4 mg/kg per day. 3. Twelve weeks following the onset of diabetes, hearts were arrested in diastole and were perfusion-fixed. The right ventricle and left ventricle plus septum were weighted and the volume of the ventricular walls was determined using the Cavalieri principle. 4. Induction of diabetes in SHR led to a significant reduction in bodyweight compared with non-diabetic control SHR and this was not affected by ramipril treatment. The development of hypertension was not as great in diabetic SHR compared with controls, such that at 12 weeks following the onset of diabetes systolic blood pressure (SBP) averaged 191 +/- 3 and 230 +/- 4 mmHg in diabetic SHR and controls, respectively. Ramipril treatment significantly lowered SBP in diabetic SHR. 5. The left ventricle plus septum volume:bodyweight ratio (LV vol:BW) was significantly higher in diabetic SHR compared with controls (3.83 +/- 0.19 and 3.26 +/- 0.16 mm3/g, respectively). Ramipril treatment did not affect growth of the left ventricle in diabetic SHR with the LV vol:BW ratio averaging 3.95 +/- 0.14 mm3/g. Similar trends on growth were observed in the right ventricle. 6. In conclusion, the development of cardiac hypertrophy in diabetic SHR appears to occur by mechanisms independent of AngII and the elevation of blood pressure.
Publisher: S. Karger AG
Date: 2004
DOI: 10.1159/000079868
Abstract: i Aim: /i This study tested the hypothesis that a nephron deficit predisposes rats to salt-sensitive hypertension in adulthood. i Methods: /i Female Wistar-Kyoto rats were fed a low (9%) or a normal (20%) protein diet during pregnancy and lactation. Male, birth-weight-matched offspring were paired. One rat from each pair was perfusion fixed at 4 weeks of age and the other rat at 40 weeks of age. Kidneys were removed and nephron number and total renal filtration surface area (FSA) determined using unbiased stereological techniques. The rats that were allowed to grow to adulthood had tail-cuff systolic blood pressure and body weight determined twice weekly. Between 30 and 40 weeks of age, a normal or a high-salt diet was fed to the rats. i Results: /i The offspring of rats fed the low-protein diet were significantly smaller at birth, and at 4 weeks of age they had a significant reduction in kidney volume, nephron number, and total renal FSA when compared to controls. Tail-cuff systolic blood pressure in the offspring from 4 to 29 weeks of age did not significantly differ between the two groups. Administration of a high-salt diet from 30 to 40 weeks of age led to a significant increase in blood pressure in both dietary treatment groups however, it was not exacerbated in the rats exposed to the low-protein diet in utero. i Conclusions: /i Maternal protein restriction in rats did not lead to salt-sensitive hypertension. Nephron endowment and FSA did not correlate with blood pressure in adulthood.
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Elsevier BV
Date: 12-0012
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.ATHEROSCLEROSIS.2005.06.036
Abstract: Limited evidence suggests that myocardial fibrosis might be associated with dietary cardiovascular risk factors. To investigate the effects of high dietary cholesterol, methionine (the precursor to homocysteine), and the combination of the two diets on myocardial fibrosis. Rabbits were randomly allocated into four dietary groups for 12 weeks: control (Con), 1% methionine (Meth), 0.5% cholesterol (Chol) or 1% methionine plus 0.5% cholesterol (MethChol). Myocardial fibrosis was not significantly increased in Chol or Meth. However, interstitial fibrosis increased by 85% (p = 0.03) and perivascular fibrosis 28-fold (p < 0.01) in the MethChol group compared to Con. These results suggest that high levels of dietary cholesterol or methionine alone do not significantly increase myocardial collagen content. However, the combination of the two diets does cause myocardial fibrosis. Therefore, excessive cholesterol and methionine intake may be an important pathogenic factor in the development of myocardial fibrosis.
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Springer Berlin Heidelberg
Date: 2008
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1046/J.1523-1755.2001.00996.X
Abstract: Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.
Publisher: Wiley
Date: 11-2014
Abstract: Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar-Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth (P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased (P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months-of-age, F1 and F2 restricted offspring had elevated blood pressure (8-15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects.
Publisher: American Physiological Society
Date: 02-2011
DOI: 10.1152/AJPHEART.00689.2010
Abstract: Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ∼145 days) tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability.
Publisher: Oxford University Press (OUP)
Date: 1997
DOI: 10.1016/S0895-7061(96)00255-5
Abstract: Intrinsic differences between vascular smooth muscle cells (VSMC) in normotension and genetic hypertension may account for the exaggerated growth response often observed in the hypertensive vasculature. To test this hypothesis, in this study we compared the vascular growth response of the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) following induction of one kidney, one clip (1KlC) renal hypertension. SHR and WKY rats were uninephrectomized and renal hypertension (RH) induced using silver clips of 0.22 and 0.24 mm width. Four weeks later, vessel and VSMC growth were assessed in small mesenteric arteries. The systolic blood pressure (SBP) in the RH animals was significantly higher than in uninephrectomised controls, in RH-SHR with a 0.24 mm clip SBP averaged 215 +/- 4 mm Hg and in RH-WKY with a 0.22 or 0.24 mm clip the SBPs averaged 214 +/- 5 mm Hg and 190 +/- 2 mm Hg, respectively. For the same SBP, there were no differences in medial cross-sectional areas of the small mesenteric arteries between RH-SHR and RH0.22-WKY, which averaged 1.73 +/- 0.19 x 10(4) microm2 and 1.66 +/- 0.15 x 10(4) microm2, respectively. Likewise, the number of VSMCs (within a precise anatomical site of the mesenteric vasculature) were not different between the RH-SHR and the RH0.22-WKY with VSMC number 7.6 +/- 0.8 x 10(4) cells and 6.9 +/- 0.4 x 10(4) cells, respectively. In the RH0.22-WKY vascular growth responses were generally unchanged compared with the RH0.24-WKY except for a further increase in the incidence of polyploid cells. In conclusion, the results of this study demonstrate that smooth muscle cells of the SHR are not hyperresponsive to all growth-promoting stimuli. Taken together with previous observations, it appears that sustained activity of the renin-angiotensin system may be required for exaggerated vascular growth responses in SHR.
Publisher: Bioscientifica
Date: 02-2017
DOI: 10.1530/JOE-16-0300
Abstract: Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic cl ) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, β-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males ( P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 ( P = 0.019), PRKAA2 ( P = 0.021) and PRKAG2 ( P = 0.049) expression was greater in preterm than in term overall and in males, while INSR ( P = 0.047) and AKT2 ( P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1997
DOI: 10.1097/00004872-199715090-00004
Abstract: To examine the role played by angiotensin II (AII) in the development of prehypertensive vascular hypertrophy in the spontaneously hypertensive rat (SHR) and to determine whether normalization of prehypertensive vascular hypertrophy attenuates the development of hypertension. Male SHR and Wistar-Kyoto (WKY) rats were treated from age 10 days until age 6 weeks with perindopril, an angiotensin converting enzyme (ACE) inhibitor, or with losartan, a type 1 AII receptor antagonist. At termination of treatment, or 8 weeks after cessation of treatment, vascular growth was assessed by measurement of hindquarter resistance properties and of the medial cross-sectional area of first-order mesenteric arteries. The growth of the heart was assessed by measurement of the left ventricle:body weight ratio. Perindopril and losartan treatment of SHR and WKY rats led to a heterogeneous response in the vasculature, resulting in a reduction in perfusion pressures at maximum dilatation and constriction in the hindquarter vasculature but no significant change in medial cross-sectional area of small mesenteric arteries. Neither perindopril nor losartan treatment affected the growth of the left ventricle in the SHR. After the cessation of treatment the development of hypertension in the losartan- and perindopril-treated SHR did not differ from that in controls. These results suggest that AII, acting via angiotensin type 1 receptors, plays an important role in determining the early post-natal reactivity of the hindquarter vasculature but not the medial cross-sectional area of the mesenteric vasculature, which implies that different growth regulatory mechanisms are operating in the two vascular beds. The lack of effect in some vascular beds, together with the lack of effect on the heart, may account for the absence of a persistent effect on the blood pressure.
Publisher: Wiley
Date: 09-11-2018
DOI: 10.1113/EP086494
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1995
DOI: 10.1097/00004872-199506000-00016
Abstract: To investigate whether angiotensin II (Ang II) exerts a direct effect on cardiovascular hypertrophy in the spontaneously hypertensive rat or acts indirectly through elevation of blood pressure. Immature (7-week-old) and mature (14-week-old) spontaneously hypertensive rats were treated for 8 and 6 weeks, respectively, with an angiotensin converting enzyme inhibitor to block the in vivo production of Ang II and concomitantly infused with either a pressor dose of Ang II or noradrenaline. At the termination of treatment, vascular smooth muscle cell growth was assessed in the aorta and mesenteric arterioles. In the young rats systolic blood pressure was not significantly different in the Ang II- and noradrenaline-infused groups. In the mature rats blood pressure was elevated in the Ang II-infused rats above that in the untreated and noradrenaline-infused groups, in which blood pressure was not significantly different. Ang II infusion induced cardiac hypertrophy and medial hypertrophy both in the aorta and in first-order mesenteric arterioles, accompanied by induction of smooth muscle polyploidy. The growth response to Ang II differed in the large and small vessels, with a marked induction of smooth muscle hyperplasia in the mesenteric arterioles but no change in cell number in the aorta. Infusion of noradrenaline did not induce cardiac or vascular hypertrophy, levels being similar to those in the rats treated with perindopril only. These results suggest that Ang II can directly stimulate cardiac and vascular hypertrophy in the spontaneously hypertensive rat, independently of its effect on blood pressure.
Publisher: Wiley
Date: 31-03-2016
DOI: 10.1111/AOGS.12880
Abstract: Preterm birth occurs in approximately 10% of all births worldwide. It prematurely exposes the developing cardiovascular system to the hemodynamic transition that occurs at birth and to the subsequent functional demands of life ex utero. This review describes the current knowledge of the effects of preterm birth, and some of its common antecedents (chorioamnionitis, intra-uterine growth restriction, and maternal antenatal corticosteroid administration), on the structure of the myocardium. A thorough literature search was conducted for articles relating to how preterm birth, and its antecedents, affect development of the heart. Given that sheep are an excellent model for the studies of cardiac development, this review has focused on experimental studies in sheep as well as clinical findings. Our review of the literature demonstrates that in iduals born preterm are at an increased risk of cardiovascular disease later in life, including increased mean arterial pressure, abnormally shaped and sub-optimally performing hearts and changes in the vasculature. The review highlights how antenatal corticosteroids, intra-uterine growth restriction, and exposure to chorioamnionitis also have the potential to impact cardiac growth in the preterm newborn. Preterm birth and its common antecedents (antenatal corticosteroids, intra-uterine growth restriction, and chorioamnionitis) have the potential to adversely impact cardiac structure immediately following birth and in later life.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2013
DOI: 10.1007/S12265-013-9475-Y
Abstract: Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, from infants to the elderly. Of particular concern is the high incidence of vitamin D deficiency in women during pregnancy and lactation, leading to the exposure of the growing fetus/infant to inadequate levels of vitamin D, which is essential for normal development. Vitamin D deficiency in adulthood is linked to the etiology of hypertension and to a multitude of adverse cardiovascular outcomes. It is now well-established that the antecedents of cardiovascular disease can originate very early in life. The purpose of this review is to highlight how maternal vitamin D deficiency, and its effects in upregulating the fetal renin-angiotensin system and altering cardiomyocyte growth in the fetal heart, has the potential to program long-term vulnerability to cardiovascular disease.
Publisher: Wiley
Date: 18-12-2018
DOI: 10.1113/JP275339
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1989
DOI: 10.1097/00004872-198912000-00011
Abstract: The angiotensin converting enzyme (ACE) inhibitor enalapril was used to examine the effects of inhibition, regression and redevelopment of hypertension on the ploidy of aortic smooth muscle cells in spontaneously hypertensive rats (SHR). The incidence of polyploidy cells, as determined by flow cytometric DNA analysis, directly paralleled changes in systolic blood pressure. When the development of hypertension was inhibited by treatment with enalapril, the incidence of polyploid cells remained low compared with untreated age-matched SHR. Likewise, when the blood pressure of hypertensive animals was lowered by enalapril treatment, the incidence of polyploid cells decreased. Addition of enalapril to primary cultures of smooth muscle had no direct effect on proliferation or the incidence of polyploidy. These results suggest that angiotensin II may be involved in the development of vascular smooth muscle polyploidy in vivo, either by a direct effect on the cells or indirectly by elevating blood pressure or by potentiation of sympathetic discharge.
Publisher: Wiley
Date: 27-10-2013
Abstract: A reduced nephron endowment early in life adversely impacts on long-term functional reserve in the kidney. A recent study has shown that acute exposure to chorioamnionitis during late gestation can adversely impact on nephrogenesis. The present study aimed to examine the effects of chronic, low-dose endotoxin exposure in utero, during the period of nephrogenesis, on nephron number and glomerular size in preterm lambs. Ewes were administered either endotoxin (lipopolysaccharide 1 mg/day) or saline at 110-133 days of gestation (term approximately 147 days) via surgically implanted osmotic minipumps within the amniotic cavity. The ewes were induced to deliver preterm at 133 days gestation and the kidneys of the lambs were analysed at 8 weeks after term-equivalent age. Nephron number per kidney was determined using a combined optical disector and fractionator stereological approach renal corpuscle size was also measured stereologically. At 8 weeks after term-equivalent age there was no significant effect of in utero exposure to endotoxin on bodyweight or kidney weight and there were no significant differences in nephron number, nephron density or renal corpuscle volume between groups. We conclude that chronic intrauterine inflammation during the period of nephrogenesis may not adversely impact on the number of nephrons formed within the kidney or on the volume of the renal corpuscle.
Publisher: American Physiological Society
Date: 05-2012
DOI: 10.1152/AJPREGU.00030.2012
Abstract: A reduced complement of cardiomyocytes in early life can adversely affect life-long cardiac functional reserve. In the present study, using a cross-fostering approach in rats, we examined the contributions of the prenatal and postnatal environments in the programming of cardiomyocyte growth. Rat dams underwent either bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of gestation. One day after birth, Control and Restricted pups were cross-fostered onto Control (normal lactation) or Restricted (impaired lactation due to impaired mammary gland formation) mothers. In male offspring, genes involved in cardiomyocyte differentiation, proliferation, hypertrophy and apoptosis were examined at gestational day 20 and postnatal days 1 and 7 to assess effects on cardiomyocyte growth. At postnatal day 7 cardiomyocyte number was determined stereologically. Offspring were examined at age 6 mo for evidence of hypertension and pathological cardiac gene expression. There was an increase in Igf1 and Igf2 mRNA expression in hearts of Restricted pups at gestational day 20. At postnatal day 7, Agtr1a and Agtr1b mRNA expression as well as Bcl2 and Cmyc were elevated in all hearts from offspring that were prenatally or postnatally growth restricted. There was a significant reduction (−29%) in cardiomyocyte number in the Restricted-on-Restricted group. Importantly, this deficit was prevented by optimization of postnatal nutrition (in the Restricted-on-Control group). At 6 mo, blood pressure was significantly elevated in the Restricted-on-Restricted group, but there was no difference in expression of the cardiac hypertrophy, remodeling or angiogenic genes across groups. In conclusion, the findings reveal a critical developmental window, when cardiomyocytes are still proliferating, whereby improved neonatal nutrition has the capacity to restore cardiomyocyte number to normal levels. These findings are of particular relevance to the preterm infant who is born at a time when cardiomyocytes are immature and still iding.
Publisher: Cambridge University Press (CUP)
Date: 06-2011
DOI: 10.1017/S0007114511001784
Abstract: Epidemiological studies have linked intra-uterine growth restriction (IUGR) with an increased risk of CVD later in life. The aim of the present study was to examine the effect of maternal protein restriction on cardiac function in adulthood during dobutamine (DOB) stimulation. IUGR was induced in Wistar Kyoto dams through administration of a low-protein diet (LPD 8·7 % casein) during pregnancy and lactation the control group received a normal-protein diet (NPD 20 % casein). At 14 weeks of age, cardiac function was assessed in male and female NPD (eight females and eight males) and LPD offspring (ten females and ten males) by pressure volumetry using an anaesthetised closed-chest approach. We determined mean arterial pressure (MAP), heart rate and left ventricular pressure–volume indices under baseline conditions and DOB stimulation (2 and 4 μg/kg per min). During β-adrenergic activation in LPD offspring, increases in cardiac output (CO, P 0·018) and stroke volume (SV, P 0·005) were attenuated in comparison with NPD offspring, while increases in ejection fraction and the maximal rate of ventricular pressure development were not affected. LPD females maintained a smaller end-diastolic volume ( P 0·017). MAP did not differ between the groups and did not change significantly during DOB infusion. Arterial elastance and total peripheral resistance decreased in all rats but remained significantly elevated in LPD offspring ( P 0·015 and 0·01). Early growth restriction did not affect ventricular contractility but led to an increased afterload and impaired the ability to increase SV and CO during β-adrenergic stimulation.
Publisher: Springer Science and Business Media LLC
Date: 06-2005
Publisher: Springer Science and Business Media LLC
Date: 04-2009
Publisher: Springer Science and Business Media LLC
Date: 09-2005
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
Publisher: American Physiological Society
Date: 15-05-2012
DOI: 10.1152/AJPRENAL.00216.2011
Abstract: Preterm neonates are commonly exposed postnatally to pharmacological treatments for a patent ductus arteriosus. Exposure of the developing kidney to nephrotoxic medications may adversely impact renal development. This study aimed to determine the effect of early postnatal ibuprofen treatment, both alone and in combination with a nitric oxide synthase inhibitor (NOSi), on renal development and morphology. Baboon neonates were delivered prematurely at 125-day (125d) gestation (term = 185d) and were euthanized at birth or postnatal day 6. Neonates were ided into four groups: 125d gestational controls ( n = 8), Untreated ( n = 8), Ibuprofen ( n = 6), and ibuprofen (Ibu)+NOSi ( n = 4). Animals in the Ibuprofen and Ibu+NOSi groups received five doses of ibuprofen, with the Ibuprofen+NOSi animals additionally administered a NOS inhibitor ( N G -monomethyl-l-arginine). There was no difference among groups in body weight, kidney weight, or glomerular generation number. Nephrogenic zone width was significantly reduced in the Ibuprofen group (123.5 ± 7.4 μm) compared with the 125d gestational control (176.1 ± 6.9 μm) and Untreated animals (169.7 ± 78.8 μm). In the Ibu+NOSi group, nephrogenic zone width averaged 152.7 ± 3.9 μm, which was not significantly different from any other group. Morphologically abnormal glomeruli were present at a range of 0.0–22.9% in the Untreated group, 0.0–6.1% in the Ibuprofen group, and 0.0–1.4% in the Ibu+NOSi group. In conclusion, early postnatal ibuprofen exposure is associated with a reduced nephrogenic zone width, which may suggest the early cessation of nephrogenesis following treatment. Ultimately, this may impact the number of nephrons formed in the preterm kidney.
No related grants have been discovered for Mary Jane Black.