ORCID Profile
0000-0002-0471-8517
Current Organisation
University of the Sunshine Coast
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Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 10-01-2012
Publisher: American Physiological Society
Date: 06-2018
DOI: 10.1152/AJPREGU.00357.2017
Abstract: There is an increased incidence of heart failure in in iduals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson’s trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.
Publisher: Wiley
Date: 05-07-2018
DOI: 10.1113/JP275918
Publisher: Springer Science and Business Media LLC
Date: 18-04-2012
DOI: 10.1007/S00441-012-1411-Y
Abstract: Adverse exposures in utero have long been linked with an increased susceptibility to adult cardio-renal and metabolic diseases. Clear gender differences exist, whereby growth-restricted females, although exhibiting some phenotypic modifications, are often protected from overt disease outcomes. One of the greatest physiological challenges facing the female gender, however, is that of pregnancy yet little research has focused on the outcomes associated with this, as a potential 'second-hit' for those who were small at birth. We review the limited evidence suggesting that pregnancy may unmask cardio-renal and metabolic disease states and the consequences for long-term maternal health in females who were born small. Additionally, a growing area of research in this programming field is in the transgenerational transmission of low birth weight and disease susceptibility. Pathways for transmission might include an abnormal adaptation to pregnancy by the growth-restricted mother and/or inheritance via the parental germline. Strategies to optimise the pregnancy environment and/or prevent the consequences of inheritance of programmed deficits and dysfunction are of critical importance for future generations.
Publisher: American Physiological Society
Date: 15-05-2012
DOI: 10.1152/AJPENDO.00583.2011
Abstract: We have previously shown that 4 wk of exercise training early in life normalizes the otherwise greatly reduced pancreatic β-cell mass in adult male rats born small. The aim of the current study was to determine whether a similar normalization in adulthood of reduced skeletal muscle mitochondrial biogenesis markers and alterations in skeletal muscle lipids of growth-restricted male rats occurs following early exercise training. Bilateral uterine vessel ligation performed on day 18 of gestation resulted in Restricted offspring born small ( P 0.05) compared with both sham-operated Controls and a sham-operated Reduced litter group. Offspring remained sedentary or underwent treadmill running from 5–9 (early exercise) or 20–24 (later exercise) wk of age. At 24 wk of age, Restricted and Reduced litter offspring had lower ( P 0.05) skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein expression compared with Control offspring. Early exercise training had the expected effect of increasing skeletal muscle markers of mitochondrial biogenesis, but, at this early age (9 wk), there was no deficit in Restricted and Reduced litter skeletal muscle mitochondrial biogenesis. Unlike our previous observations in pancreatic β-cell mass, there was no “reprogramming” effect of early exercise on adult skeletal muscle such that PGC-1α was lower in adult Restricted and Reduced litter offspring irrespective of exercise training. Later exercise training increased mitochondrial biogenesis in all groups. In conclusion, although the response to exercise training remains intact, early exercise training in rats born small does not have a reprogramming effect to prevent deficits in skeletal muscle markers of mitochondrial biogenesis in adulthood.
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.PLACENTA.2016.12.006
Abstract: Maternal obesity is growing in prevalence and is associated with increased morbidity and mortality for both mother and child. Women who are obese during pregnancy have a greater risk of metabolic complications such as gestational diabetes mellitus (GDM) as well as type 2 diabetes after pregnancy. Children of obese and/or GDM mothers have an increased susceptibility to congenital abnormalities and a range of cardio-metabolic disorders. The placenta is at the interface of the maternal and fetal environments and, its function per se, plays a major role in dictating the impact of maternal health on fetal development. Here, we review the literature on how placental function is affected in pregnancies complicated by obesity, and pre-gestational and gestational diabetes. The focus is on the availability of three key substrates in these conditions: glucose, lipids, and amino acids, and their impact on placental metabolic activity. Maternal obesity and diabetes are not always associated with fetal compromise and the adaptation of the placenta may partially determine the outcome. Understanding the differences in metabolic adaptation may open avenues for therapeutic development.
Publisher: Wiley
Date: 06-07-2012
DOI: 10.1096/FJ.12-210401
Abstract: Uteroplacental insufficiency is associated with adult cardiorenal and metabolic diseases, particularly in males. Pregnancy is the greatest physiological challenge facing women, and those born small are at increased risk of gestational hypertension and diabetes and delivering smaller babies. Increased maternal age is associated with exacerbated pregnancy complications. We hypothesized that pregnancy in aged, growth-restricted females unmasks an underlying predisposition to cardiorenal and metabolic dysfunction and compromises fetal growth. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted group) or sham surgery (control group) on d 18 of gestation in Wistar Kyoto rats. At 12 mo, growth-restricted F1 female offspring were mated with a normal male. F1 restricted females had elevated systolic blood pressure, before and during pregnancy (+10 mmHg) but normal renal and metabolic pregnancy adaptations. F2 fetal weight was not different between groups. In control and restricted females, advanced maternal age (12 vs. 4 mo) was associated with a reduction in the hypoglycemic response to pregnancy and reduced F2 fetal litter size and body weight. Aged rats born small exhibited mostly normal pregnancy adaptations, although they had elevated blood pressure. Advanced maternal age was associated with poorer fetal outcomes that were not exacerbated by low maternal birth weight.
Publisher: American Physiological Society
Date: 11-2011
DOI: 10.1152/AJPENDO.00114.2011
Abstract: Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60–68% deficit ( P 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit ( P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease.
Publisher: American Diabetes Association
Date: 28-01-2016
DOI: 10.2337/DB15-0864
Abstract: Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2014
DOI: 10.1007/S00125-014-3291-Z
Abstract: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.
Publisher: eLife Sciences Publications, Ltd
Date: 22-07-2020
DOI: 10.7554/ELIFE.56907
Abstract: Diabetes mellitus is a known susceptibility factor for severe influenza virus infections. However, the mechanisms that underlie this susceptibility remain incompletely understood. Here, the effects of high glucose levels on influenza severity were investigated using an in vitro model of the pulmonary epithelial-endothelial barrier as well as an in vivo murine model of type II diabetes. In vitro we show that high glucose conditions prior to IAV infection increased virus-induced barrier damage. This was associated with an increased pro-inflammatory response in endothelial cells and the subsequent damage of the epithelial junctional complex. These results were subsequently validated in vivo . This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in in iduals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections.
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: Cold Spring Harbor Laboratory
Date: 15-05-2020
DOI: 10.1101/2020.05.10.20076414
Abstract: The pandemic inflicted by coronavirus disease 2019 (COVID-19) resulted in physical isolation measures in many parts of the world. In Australia, nationwide restrictions included staying at home, unless seeking medical care, providing care, purchasing food, undertaking exercise, or attending work in an essential service. All undergraduate university classes transitioned to online, mostly home-based learning. This disruption to daily life may have consequences for eating and physical activity patterns. In this observational study, we examined the effect of isolation measures, during the early phase of the COVID-19 pandemic in Australia (March/April), on diet (24-hour diet recall, ASA-24) and physical activity (Active Australia Survey) patterns among third-year biomedical students in Brisbane, Australia. Findings were compared to students enrolled in the same course in the previous two years. In females, energy intake was ~20% greater in 2020 compared with 2018 and 2019, and the frequency of snacking and energy density of consumed snacks were also increased. In males, there was no difference in energy intake or snacking behaviour. Physical activity was impacted for both sexes, whereby fewer students undertook any walking activity and, of those that did, time spent doing so was less compared with 2018 and 2019. The proportion of students reporting any vigorous activity was not different for males or females but, among males who participated in this level of activity, the duration was less in 2020 compared with previous years. The proportion of male and female students achieving ‘sufficient’ levels of activity, defined by at least 150 mins over at least 5 sessions, was ~30% less in 2020. Indeed, the majority of students reported as having undertaken less physical activity than usual. Increased energy intake for females and reduced physical activity for males and females demonstrate impacts of isolation measures that may have deleterious consequences for physical and mental wellbeing, with the potential to affect long-term nutrition and activity patterns.
Publisher: Wiley
Date: 25-04-2018
DOI: 10.1113/JP275655
Publisher: MDPI AG
Date: 22-04-2022
DOI: 10.3390/ANTIBIOTICS11050557
Abstract: With the uncontrolled growth of multidrug-resistant bacteria, there is an urgent need to search for new therapeutic targets, to develop drugs with novel modes of bactericidal action. FoF1-ATP synthase plays a crucial role in bacterial bioenergetic processes, and it has emerged as an attractive antimicrobial target, validated by the pharmaceutical approval of an inhibitor to treat multidrug-resistant tuberculosis. In this work, we aimed to design, through two types of in silico strategies, new allosteric inhibitors of the ATP synthase, by targeting the catalytic β subunit, a centerpiece in communication between rotor subunits and catalytic sites, to drive the rotary mechanism. As a model system, we used the F1 sector of Escherichia coli, a bacterium included in the priority list of multidrug-resistant pathogens. Drug-like molecules and an IF1-derived peptide, designed through molecular dynamics simulations and sequence mining approaches, respectively, exhibited in vitro micromolar inhibitor potency against F1. An analysis of bacterial and Mammalia sequences of the key structural helix-turn-turn motif of the C-terminal domain of the β subunit revealed highly and moderately conserved positions that could be exploited for the development of new species-specific allosteric inhibitors. To our knowledge, these inhibitors are the first binders computationally designed against the catalytic subunit of FOF1-ATP synthase.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2021
DOI: 10.1038/S41598-021-88786-4
Abstract: To examine if skin autofluorescence (sAF) differed in early adulthood between in iduals with type 1 diabetes and age-matched controls and to ascertain if sAF aligned with risk for kidney disease. Young adults with type 1 diabetes ( N = 100 20.0 ± 2.8 years M:F 54:46 FBG-11.6 ± 4.9 mmol/mol diabetes duration 10.7 ± 5.2 years BMI 24.5(5.3) kg/m 2 ) and healthy controls ( N = 299 20.3 ± 1.8 years M:F-83:116 FBG 5.2 ± 0.8 mmol/L BMI 22.5(3.3) kg/m 2 ) were recruited. Skin autofluorescence (sAF) and circulating AGEs were measured. In a subset of both groups, kidney function was estimated by GFR CKD-EPI CysC and uACR, and DKD risk defined by uACR tertiles. Youth with type 1 diabetes had higher sAF and BMI, and were taller than controls. For sAF, 13.6% of variance was explained by diabetes duration, height and BMI ( P model = 1.5 × 10 –12 ). In the sub-set examining kidney function, eGFR and sAF were higher in type 1 diabetes versus controls. eGFR and sAF predicted 24.5% of variance in DKD risk ( P model = 2.2 × 10 –9 ), which increased with diabetes duration (51% P model 2.2 × 10 –16 ) and random blood glucose concentrations (56% P model 2.2 × 10 –16 ). HbA 1C and circulating fructosamine albumin were higher in in iduals with type 1 diabetes at high versus low DKD risk. eGFR was independently associated with DKD risk in all models. Higher eGFR and longer diabetes duration are associated with DKD risk in youth with type 1 diabetes. sAF, circulating AGEs, and urinary AGEs were not independent predictors of DKD risk. Changes in eGFR should be monitored early, in addition to uACR, for determining DKD risk in type 1 diabetes.
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/RD13133
Abstract: A developmental insult that restricts growth in the first generation has the potential to program disease in subsequent generations. The aim of this study was to ascertain transgenerational growth and cardio–renal effects, via the maternal line, in a rat model of utero–placental insufficiency. Bilateral uterine vessel ligation or sham surgery (offspring termed first generation F1 Restricted and Control, respectively) was performed in WKY rats. F1 Restricted and Control females were mated with normal males to produce second generation (F2) offspring (Restricted and Control) studied from fetal (embryonic Day 20) to adult (12 months) life. F2 Restricted male and female fetuses had reduced (P 0.05) nephron number (down 15–22%) but this deficit was not sustained postnatally and levels were similar to Controls at Day 35. F2 Restricted males, but not females, developed elevated (+16 mmHg, P 0.05) systolic blood pressure at 6 months of age, which was sustained to 9 months. This was not explained by alterations to intra-renal or plasma components of the renin–angiotensin system. In a rat model of utero–placental insufficiency, we report alterations to F2 kidney development and sex-specific adult hypertension. This study demonstrates that low birthweight can have far-reaching effects that extend into the next generation.
Publisher: Frontiers Media SA
Date: 22-05-2017
Publisher: Wiley
Date: 26-07-2018
DOI: 10.1113/JP275758
Publisher: Wiley
Date: 20-05-2019
DOI: 10.1113/JP277815
Publisher: MDPI AG
Date: 23-06-0006
DOI: 10.3390/NU12061865
Abstract: The coronavirus disease 2019 (COVID-19) pandemic resulted in physical isolation measures in many parts of the world. In Australia, nationwide restrictions included staying at home, unless seeking medical care, providing care, purchasing food, undertaking exercise, or attending work in an essential service. All undergraduate university classes transitioned to online, mostly home-based learning. We, therefore, examined the effect of isolation measures during the early phase of the COVID-19 pandemic in Australia (March/April) on diet (24-h recall) and physical activity (Active Australia Survey) patterns in third-year biomedical students. Findings were compared with students enrolled in the same course in the previous two years. In females, but not males, energy intake was ~20% greater during the pandemic, and snacking frequency and energy density of consumed snacks also increased compared with 2018 and 2019. Physical activity was impacted for both sexes during the pandemic with ~30% fewer students achieving “sufficient” levels of activity, defined by at least 150 min over at least five sessions, compared with the previous two years. In a follow-up study six to eight weeks later (14–18% response rate), during gradual easing of nationwide restrictions albeit continued gym closures and online learning, higher energy intake in females and reduced physical activity levels in both sexes persisted. These data demonstrate the health impacts of isolation measures, with the potential to affect long-term diet and activity behaviours.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26428
Abstract: Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db / db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
DOI: 10.1007/S43032-020-00413-1
Abstract: Maternal alcohol consumption during pregnancy results in elevated vulnerability to intrauterine growth restriction, preterm birth, miscarriage, and stillbirth. Many of the detrimental effects of fetal alcohol exposure may be mediated through placental dysfunction however, the exact mechanisms remain unknown. Here, we aimed to determine the effect of maternal alcohol exposure prior to and during early pregnancy on placental glucocorticoid receptor (GR) isoforms, associated GR regulated genes, and infant outcomes. Participants carrying singleton fetuses (n = 113) were recruited during early pregnancy. Amount and type of alcohol consumed over the last 12 months were obtained at 18 weeks of gestation. The level of drinking was separated into none (0 g/day), low ( 100 g/day). At delivery, placental weight, infant sex, birthweight, and head circumference were recorded. Placental GR isoforms and genes involved in downstream signalling pathways were quantified. The majority of women (70.8%) consumed alcohol. Of these, most consumed low (48.8%) or moderate (37.5%) amounts. Placental weight was unaffected by alcohol consumption, but infants born to heavy drinkers tended to be lighter at birth. In female, but not male, placentae, maternal alcohol consumption resulted in increased GRαC and decreased GRαD1 cytoplasmic expression. In both female and male placentae, a d ened inflammatory response was evident with maternal alcohol consumption, involving downregulated IL6R and upregulated POU2F2 gene expression, respectively. Maternal alcohol consumption in the months prior to, and/or during early, pregnancy alters placental GR isoform and expression of some inflammatory genes in a sex-specific manner.
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.PLACENTA.2016.12.012
Abstract: The aetiology of many gestational disorders is still unknown. However, insufficient trans-placental nutrient and oxygen transfer due to abnormal placentation is characteristic of several pathologies, and may alter the function of placental mitochondria. Mitochondria are multifunctional organelles that respond to a wide range of stimuli - such as physiological changes in cellular energy demands or various pathologies - by reshaping via fusion or fission, increasing/decreasing in number, altering oxidative phosphorylation, and signalling cellular functions such as apoptosis. Mitochondrial function is integral to tissue functions including energy production, metabolism, and regulation of various cellular responses including response to oxidative stress. This review details the functions of placental mitochondria and investigates mitochondrial function and structure in gestational disorders including preecl sia, intrauterine growth restriction, diabetes mellitus, and obesity. Placental mitochondrial dysfunction may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health.
Publisher: Wiley
Date: 27-10-2013
Abstract: Suboptimal conditions in utero are associated with the development of adult-onset diseases in offspring. Uteroplacental insufficiency in rats is a well-established animal model used to mimic and study the effects of developmental insults relevant to countries of abundant nutrient supply. However, wide-ranging outcomes for the offspring are apparent between the different investigators that use this model and also between cohorts generated in our laboratory. We aimed to explore the reasons for variability in rat models of uteroplacental insufficiency between different investigators and also between our own animal cohorts. We suggest differences in growth and disease development reflect uniqueness in susceptibility and highlight the complexity of interactions between genetic potential and environmental exposures. The impact of adverse exposures in utero has been described as having far-reaching effects that extend well beyond the first, directly exposed generation. However, the resulting phenotypes are not consistent between generations. This suggests that programmed effects are established de novo in each generation and challenges the prediction of disease. Characterization of growth and disease in the numerous rat models has led to our understanding of the impact of early life experiences on adult health. In order to drive the development of preventative and/or treatment strategies, future studies should focus on identifying the initial cause(s) of uteroplacental insufficiency, including genetic origins and the influence of poor diets.
Publisher: Bentham Science Publishers Ltd.
Date: 03-08-2016
DOI: 10.2174/1389450116666150727114410
Abstract: Mitochondria produce the majority of cellular energy via the "slow burn" of substrates such as glucose, free fatty acids and ketones. In diabetes, altered mitochondrial energetics and substrate utilisation may explain, in part, an organ's susceptibility to complications. This is particularly evident at sites such as the kidney, heart, neurons and retina, which have high energy demands and oxygen consumption rates to meet functional requirements. Within this review we highlight the recent research implicating mitochondrial dysfunction, with particular focus on the contribution of mitochondrial reactive oxygen species, on the development and progression of diabetes complications. Finally, we discuss the current strategies which are being assessed to combat mitochondrial dysfunction in diabetes complications.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2019
DOI: 10.1038/S41598-017-15589-X
Abstract: Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D) (ii) MitoQ (DMitoQ .6 mg/kg/day) (iii) Ramipril (DRam mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db / db mice for 12 weeks ( n = 11–13/group). Non-diabetic (C) db / m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown.
Publisher: MDPI AG
Date: 10-08-2022
Abstract: Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in in iduals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or in iduals with diabetes but without kidney disease (DC), in iduals with DKD (age ~55 years diabetes duration ~15 years) had evidence of mitochondrial dysfunction. In iduals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include in iduals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.
Publisher: Bioscientifica
Date: 18-02-2013
DOI: 10.1530/JOE-12-0560
Abstract: Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (−35%), which was associated with reduced pancreatic β-cell mass (−29%). By contrast, F2 restricted females had increased β-cell mass despite reduced first-phase insulin response (−38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.
Publisher: American Society for Microbiology
Date: 28-04-2020
Abstract: Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2020
DOI: 10.1101/2020.11.24.20237529
Abstract: To compare the prevalence of live preterm birth rates during COVID-19 restriction measures with infants born during the same weeks in 2013-2019 in Queensland, Australia. Deidentified obstetric and neonatal data were extracted from the Mater Mothers’ electronic healthcare records database. This is a supra-regional tertiary perinatal centre. Logistic regressions were used to examine preterm birth rates during the beginning of COVID-19 restrictions (16 March-17 April “early” 6,955 births) and during the strictest part of COVID-19 restrictions (30 March-1 May “late” 6,953 births), according to gestational age subgroups and birth onset (planned or spontaneous). We adjusted for multiple covariates, including maternal age, body mass index, ethnicity, parity, socioeconomic status, maternal asthma, diabetes mellitus and/or hypertensive disorder. Stillbirth rates were also examined (16 March-1 May). A reduction in planned moderate/late preterm births was observed primarily during the early restriction period compared with the same calendar weeks in the previous seven years (29 versus an average of 64 per 1,000 births adjusted odds ratio [aOR] 0.39, 95% CI 0.22-0.71). There was no effect on extremely or very preterm infants, spontaneous preterm births, or stillbirth rates. Rolling averages from January to June revealed a two-week non-significant spike in spontaneous preterm births from late-April to early-May, 2020. Planned births for moderate/late preterm infants more than halved during early COVID-19 mitigation measures. Together with evidence from other nations, the COVID-19 pandemic provides a unique opportunity to identify causal and preventative factors for preterm birth.
Publisher: CRC Press
Date: 30-10-2017
Publisher: MDPI AG
Date: 03-10-2021
DOI: 10.3390/NU13103500
Abstract: There is a paucity of data on whether Australian university students are meeting specific nutrient guidelines, and the relationship between diet and physical activity patterns with body composition and metabolic health. In this study, biomedical students from The University of Queensland were recruited (150 males and 211 females, 19–25 years), and nutritional intake (ASA24-Australia) and physical activity levels (Active Australia Survey) quantified. Body composition (height, waist circumference, body mass, BMI, and percentage body fat BOD POD) and metabolic health (oral glucose tolerance test) were also measured. Median daily energy intake was 6760 kJ in females and 10,338 kJ in males, with more than 30% of total energy coming from energy-dense, nutrient-poor foods. Only 1 in 10 students met fruit or vegetable recommendations, with less than one third meeting recommendations for fibre, calcium, and potassium. Intakes of calcium and iron were particularly low among female students, with only 16% and 6% of students meeting the recommended dietary intake (RDI), respectively. The majority of males and almost half of all females exceeded the suggested dietary target (SDT) for sodium. Sufficient physical activity (≥150 min over ≥5 sessions per week) was met by more than 80% of students. Body composition and blood glucose concentrations were largely normal but an early sign of insulin resistance (HOMA-IR 2.0), measured in a subset of students, was present in 21% of males and 17% of females. Modest reductions in blood glucose levels and percentage body fat were associated with increasing vigorous activity. Low intakes of fibre, calcium, and potassium could be corrected by increasing fruit, vegetable, and dairy intake, and, among females, health promotion messages focusing on iron-rich foods should be prioritised. While these nutrient deficiencies did not translate into immediate metabolic heath concerns, dietary behaviours can track into adulthood and have lasting effects on overall health.
Publisher: Wiley
Date: 12-07-2022
DOI: 10.1111/AJO.13406
Abstract: Reports from around the world suggest that rates of preterm birth decreased during COVID‐19 lockdown measures. To compare the prevalence of preterm birth and stillbirth rates during COVID‐19 restriction measures with infants born at the same maternity centre during the same weeks in 2013–2019. Deidentified data were extracted from the Mater Mothers’ healthcare records database. This is a supra‐regional tertiary perinatal centre. Logistic regressions were used to examine singleton live preterm birth rates during the beginning of COVID‐19 restrictions (16 March‐17 April ‘early’ 6955 births) and during the strictest part of COVID‐19 restrictions (30 March‐1 May ‘late’ 6953 births), according to gestational age subgroups and birth onset (planned or spontaneous). We adjusted for multiple covariates, including maternal age, body mass index, ethnicity, parity, socioeconomic status, maternal asthma, diabetes mellitus and/or hypertensive disorder. Singleton stillbirth rates were also examined between 16 March–1 May. Planned moderate/late preterm births declined by more than half during early COVID‐19 restrictions compared with the previous seven years (29 vs an average of 64 per 1000 births adjusted odds ratio 0.39, 95% CI 0.22–0.71). There was no effect on extremely or very preterm infants, spontaneous preterm births, or stillbirth rates. Rolling averages from January to June revealed a two‐week non‐significant spike in spontaneous preterm births from late April to early May, 2020. Together with evidence from other nations, the pandemic provides a unique opportunity to identify causal and preventative factors for preterm birth.
Publisher: Cold Spring Harbor Laboratory
Date: 15-08-2020
DOI: 10.1101/2020.08.15.252593
Abstract: Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in non-diabetic and diabetic mice with cardiac pressure overload. Five-week old male C57BL/6J mice were randomized to receive a high fat diet (HFD 60% of calories from fat) to induce diabetes or remain on normal diet (ND) for 12 weeks. Transverse aortic constriction (TAC) was then employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in features representative of heart failure with preserved ejection fraction. At five weeks into the dietary protocol, mice were treated for seven weeks by oral gavage once daily with sotagliflozin (10mg/kg body weight) or vehicle (0.1% tween 80). In ND non-diabetic mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilisation nor increased cardiac ketolysis. In HFD diabetic mice, sotagliflozin did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound diuresis and glucosuria, which may have compromised drug action and subsequent cardio-protection. We demonstrate the utility of dual SGLT1/2 inhibition in treating heart failure risk factors in the non-diabetic state. Its efficacy in high fat-induced diabetes with proximal tubular damage requires further study.
Publisher: Informa UK Limited
Date: 22-12-2017
Publisher: Cambridge University Press (CUP)
Date: 19-07-2010
DOI: 10.1017/S2040174410000383
Abstract: Uteroplacental insufficiency and poor postnatal nutrition impair adult glucose tolerance and insulin secretion in male rat offspring, which can be partially ameliorated by improving postnatal nutrition. Uteroplacental insufficiency was induced in the WKY rat on day 18 of pregnancy ( Restricted ) compared to sham-operated Controls . Pups were then cross-fostered onto Control or Restricted mothers one day after birth resulting in: ( Pup -on- Mother ) Control -on- Control , Control -on- Restricted , Restricted -on- Control and Restricted -on- Restricted. Endocrine pancreatic morphology and markers of intrinsic β-cell function and glucose homeostasis were assessed in male offspring at 6 months. Pancreatic and hepatic gene expression was quantified at postnatal day 7 and 6 months. Restricted pups were born 10–15% lighter than Controls and remained lighter at 6 months. Relative islet and β-cell mass were 51–65% lower in Restricted -on- Restricted compared to Controls at 6 months. Non-fasting plasma C-reactive protein levels were also increased, suggestive of an inflammatory response. Overall, the average number of islets, small islets and proportion of β-cells per islet correlated positively with birth weight. Intrinsic β-cell function, estimated by insulin secretion relative to β-cell mass, was unaffected by Restriction , suggesting that the in vivo functional deficit was attributable to reduced mass, not function. Importantly, these deficits were ameliorated when lactational nutrition was normalized in Restricted -on- Control offspring, who also showed increased pancreatic Igf1r, Pdx1 and Vegf mRNA expression at 7 days compared to Control -on- Control and Restricted -on- Restricted . This highlights lactation as a critical period for intervention following prenatal restraint, whereby deficits in endocrine pancreatic mass and associated impaired in vivo insulin secretion can be ameliorated.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.KINT.2019.04.031
Abstract: Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12 these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene Ark1b3, coding aldose reductase the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
DOI: 10.1161/HYPERTENSIONAHA.112.195578
Abstract: Intrauterine growth restriction is associated with increased risk of adult cardiorenal diseases. Small birth weight females are more likely to experience complications during their own pregnancy, including pregnancy-induced hypertension, preecl sia, and gestational diabetes. We determined whether the physiological demand of pregnancy predisposes growth-restricted females to cardiovascular and renal dysfunction later in life. Late gestation bilateral uterine vessel ligation was performed in Wistar-Kyoto rats. At 4 months, restricted and control female offspring were mated with normal males and delivered naturally (ex-pregnant). Regardless of maternal birth weight, at 13 months, ex-pregnant females developed elevated mean arterial pressure (indwelling tail-artery catheter +6 mm Hg), reduced effective renal blood flow ( 14 C-PAH clearance −23%), and increased renal vascular resistance (+27%) compared with age-matched virgins. Glomerular filtration rate ( 3 H-inulin clearance) was not different across groups. This adverse cardiorenal phenotype in ex-pregnant females was associated with elevated systemic (+57%) and altered intrarenal components of the renin-angiotensin system. After pregnancy at 13 months, coronary flow (Langendorff preparation) was halved in restricted females compared with controls, and together with reduced NO excretion, this may increase susceptibility to additional lifestyle challenges. Our results have implications for aging females who have been pregnant, suggesting long-term cardiovascular and renal alterations, with additional consequences for females who were small at birth.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.BONE.2015.01.018
Abstract: Low birth weight, due to uteroplacental insufficiency, results in programmed bone deficits in the first generation (F1). These deficits may be passed onto subsequent generations. We characterized the effects of being born small on maternal bone health during pregnancy and aimed to characterize the contribution of the maternal environment and germ line effects to bone health in F2 offspring from mothers born small. Bilateral uterine vessel ligation (or sham) surgery was performed on female F0 WKY rats on gestational day 18 (term 22days) to induce uteroplacental insufficiency and fetal growth restriction. Control and Restricted F1 female offspring were allocated to a non-pregnant or pregnant group. To generate F2 offspring, F1 females were allocated to either non-embryo or embryo transfer groups. Embryo transfer was performed on gestational day 1, where second generation (F2) embryos were gestated (donor-in-recipient) in either a Control (Control-in-Control, Restricted-in-Control) or Restricted (Control-in-Restricted, Restricted-in-Restricted) mother. Restricted F1 females were born 10-15% lighter than Controls. Restricted non-pregnant females had shorter femurs, reduced trabecular and cortical bone mineral contents, trabecular density and bone geometry measures determined by peripheral quantitative computed tomography (pQCT) compared to non-pregnant Controls. Pregnancy restored the bone deficits that were present in F1 Restricted females. F2 non-embryo transfer male and female offspring were born of normal weight, while F2 embryo transfer males and females gestated in a Control mother (Control-in-Control, Restricted-in-Control) were heavier at birth compared to offspring gestated in a Restricted mother (Restricted-in-Restricted, Control-in-Restricted). Male F2 Restricted embryo groups (Restricted-in-Control and Restricted-in-Restricted) had accelerated postnatal growth. There was no transmission of bone deficits present at 35days or 6months in F2 offspring. Embryo transfer procedure had confounding effects preventing the separation of maternal environment and germ line contribution to outcomes. Deficits present in F1 non-pregnant Restricted females were absent during late gestation, indicating that pregnant F1 Restricted females experienced gains in bone. These beneficial maternal pregnancy adaptations may have prevented transmission of bone deficits to F2 offspring.
Publisher: SAGE Publications
Date: 23-01-2015
Abstract: Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.
Publisher: Wiley
Date: 29-03-2020
DOI: 10.1111/NEP.13713
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.PHRS.2018.06.001
Abstract: Inhibition of the renin-angiotensin system in early postnatal life is a potential therapeutic approach to prevent long-term cardiovascular and kidney diseases in in iduals born small. We determined the long-term effects of juvenile losartan treatment on cardiovascular and kidney function in control male rat offspring and those exposed to uteroplacental insufficiency and born small. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed in late gestation in Wistar Kyoto rats. At weaning, male offspring were randomly assigned to receive losartan in their drinking water or drinking water alone from 5 to 8 weeks of age, and followed to 26 weeks of age. Systolic blood pressure and kidney function were assessed throughout the study. Pressure myography was used to assess passive mechanical wall properties in mesenteric and femoral arteries from 26-week-old offspring. Losartan treatment for three weeks lowered systolic blood pressure in both Control and Restricted groups but this difference was not sustained after the cessation of treatment. Losartan, irrespective of birth weight, mildly increased renal tubulointerstitial fibrosis when assessed at 26 weeks of age. Mesenteric artery stiffness was increased by the early losartan treatment, and was associated with increased collagen and decreased elastin content. Losartan also exerted long-term increases in fat mass and decreases in skeletal muscle mass. In this study, untreated Restricted offspring did not develop hypertension, vascular dysfunction or kidney changes as anticipated. Regardless, we demonstrate that short-term losartan treatment in the juvenile period negatively affects postnatal growth, and kidney and vascular parameters in adulthood, irrespective of birth weight. The long-term effects of early-life losartan treatment warrant further consideration in settings where the potential benefits may outweigh the risks i.e. when programmed adulthood diseases are apparent and in childhood cardiovascular and kidney diseases.
Publisher: Public Library of Science (PLoS)
Date: 13-09-2012
Publisher: American Physiological Society
Date: 15-04-2014
DOI: 10.1152/AJPREGU.00523.2013
Abstract: Adverse conditions in utero can have transgenerational effects, in the absence of a subsequent insult. We aimed to investigate the contribution of the maternal pregnancy environment vs. germ line effects in mediating alterations to cardiorenal and metabolic physiology in offspring from mothers born small. Uteroplacental insufficiency was induced by bilateral uterine artery and vein ligation (Restricted group) or sham surgery (Control group) in Wistar-Kyoto rats. Restricted and control female offspring (F1) were mated with either breeder males (embryo donor) or vasectomized males (embryo recipient). Embryo transfer was performed at embryonic day (E) 1, whereby second-generation (F2) embryos gestated (donor-in-recipient) in either a control (Cont-in-Cont, Rest-in-Cont) or restricted (Cont-in-Rest, Rest-in-Rest) mother. In male and female offspring, glomerular number and size were measured at postnatal day (PN) 35, and systolic blood pressure, glucose control, insulin sensitivity, and pancreatic β-cell mass were measured in separate sibling cohorts at 6 mo. Rest-in-Rest offspring were hypothesized to have similar characteristics (reduced growth, altered metabolic control, and hypertension) to non-embryo-transferred Rest, such that embryo transfer would not be a confounding experimental influence. However, embryo-transferred Rest-in-Rest offspring underwent accelerated growth during the peripubertal phase, followed by slowed growth between 2 and 3 mo of age compared with non-embryo-transferred Rest groups. Furthermore, renal function and insulin response to a glucose load were different to respective non-embryo-transferred groups. Our data demonstrate the long-term effects of in vitro embryo manipulation, which confounded the utility of this approach in delineating between the maternal pregnancy environment and germ line effects that drive transgenerational outcomes.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.SEMNEPHROL.2018.01.001
Abstract: The kidneys are highly metabolic organs that produce vast quantities of adenosine triphosphate via oxidative phosphorylation and, as such, contain many mitochondria. Although mitochondrial reactive oxygen species are involved in many physiological processes in the kidneys, there is a plethora of evidence to suggest that excessive production may be a pathologic mediator of many chronic kidney diseases, including diabetic kidney disease. Despite this, results from clinical testing of antioxidant therapies have been generally underwhelming. However, given the many roles of mitochondria in cellular functioning, pathways other than reactive oxygen species production may prevail as pathologic mediators in diabetic kidney disease. Accordingly, in this review, mitochondrial dysfunction in a broader context is discussed, specifically focusing on mitochondrial respiration and oxygen consumption, intrarenal hypoxia, oxidative stress, mitochondrial uncoupling, and networking.
Start Date: 2012
End Date: 2012
Funder: University of Melbourne
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: Diabetes Australia
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: National Heart Foundation of Australia
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Heart Foundation of Australia
View Funded Activity