SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption

© 2018 the American Physiological Society. Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined

Sirt1 attenuates kidney disorders in male offspring due to maternal high-fat diet

© 2019, MDPI AG. All rights reserved. Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury

Maternal L-carnitine supplementation ameliorates renal underdevelopment and epigenetic changes in male mice offspring due to maternal smoking

© 2018 John Wiley & Sons Australia, Ltd Objectives: Epidemiological and animal studies showed that L-carnitine (LC) supplementation can ameliorate oxidative stress-induced tissues damage. We have previously shown that maternal cigarette smoke exposure (SE) can increase renal oxidative stress in newborn offspring with postnatal kidney underdevelopment and renal dysfunction in adulthood, which were normalised by LC administration in the SE dams during pregnancy. Exposure to an adverse intrauterine environment may lead to alteration in the epigenome, a mechanism by which adverse prenatal conditions increase the susceptibility to chronic disease later in life. The current study aimed to determine whether maternal SE induces epigenetic changes in the offspring's kidney are associated with renal underdevelopment, and the protective effect of maternal LC supplementation. Method: Female Balb/c mice (7 weeks) were exposed to cigarette smoke (SE) or air (Sham) for 6 weeks prior to mating, during gestation and lactation. A subgroup of the SE dams received LC via drinking water (SE + LC, 1.5 mmol/L) throughout gestation and lactation. Male offspring were studied at postnatal day (P)1, P20, and 13 weeks. Results: Maternal SE altered the expression of renal development markers glial cell line-derived neurotrophic factor and fibroblast growth factor 2, which were associated with increased renal global DNA methylation and DNA methyltransferase 1 mRNA expression at birth. These disorders were reversed by maternal LC administration. Conclusion: The effect of maternal SE on renal underdevelopment involves global epigenetic alterations from birth, which can be prevented by maternal LC supplementation

Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet

BACKGROUND: Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring. METHODS: C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32. RESULTS: In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring. CONCLUSION: Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption

Novel Role of Gestational Hydralazine in Limiting Maternal and Dietary Obesity-Related Chronic Kidney Disease

Background: Maternal obesity is a risk factor for chronic kidney disease (CKD) in offspring, underpinning the theory of the developmental origins of health and disease. DNA methylation has been implicated in the programming of adult chronic disease by maternal obesity, therefore, DNA demethylating agents may mitigate offspring risk of disease. In rodent models, low-dose hydralazine has previously been shown to reduce renal fibrosis via DNA demethylation. We used mouse models of maternal obesity and offspring obesity to determine whether administration of low-dose hydralazine during gestation can prevent fetal programming of CKD in offspring. Methods: Female C57BL/6 mice received high fat diet (HFD) or chow prior to mating, during gestation and lactation. During gestation, dams received subcutaneous hydralazine (5 mg/kg) or saline thrice-weekly. Male offspring weaned to HFD or chow, which continued until endpoint at 32 weeks. Biometric and metabolic parameters, renal global DNA methylation, renal functional and structural changes, and renal markers of fibrosis, inflammation and oxidative stress were assessed at endpoint. Results: Offspring exposed to maternal obesity or diet-induced obesity had significantly increased renal global DNA methylation, together with other adverse renal effects including albuminuria, glomerulosclerosis, renal fibrosis, and oxidative stress. Offspring exposed to gestational hydralazine had significantly reduced renal global DNA methylation. In obese offspring of obese mothers, gestational hydralazine significantly decreased albuminuria, glomerulosclerosis, and serum creatinine. Obese offspring of hydralazine-treated lean mothers displayed reduced markers of renal fibrosis and oxidative stress. Conclusion: Gestational hydralazine decreased renal global DNA methylation and exerted renoprotective effects in offspring. This supports a potential therapeutic effect of hydralazine in preventing maternal obesity or dietary obesity-related CKD, through an epigenetic mechanism

Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse.

Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration

Low-dose hydralazine reduces albuminuria and glomerulosclerosis in a mouse model of obesity-related chronic kidney disease.

BACKGROUND: Obesity is a major risk factor for the development and progression of chronic kidney disease (CKD). DNA methylation has been implicated in the progression of CKD to end stage kidney disease. Drugs modifying DNA methylation, such as low-dose hydralazine, may reduce CKD progression. Using a mouse model of obesity, we aimed to determine whether low-dose hydralazine prevents obesity-related CKD. METHODS: From 8 weeks of age, male C57BL/6 mice received high fat diet (HFD) or chow, with or without low-dose hydralazine (25 mg/L) in drinking water for 24 weeks. Biometric and metabolic parameters, renal functional and structural changes, renal global DNA methylation, DNA methylation profile and markers of renal fibrosis, injury, inflammation and oxidative stress were assessed. RESULTS: HFD-fed mice developed obesity, with glucose intolerance, hyperinsulinaemia and dyslipidaemia. Obesity increased albuminuria and glomerulosclerosis, which were significantly ameliorated by low-dose hydralazine in the absence of a blood pressure-lowering effect. Obesity increased renal global DNA methylation and this was attenuated by low-dose hydralazine. HFD-induced changes in methylation of individual loci were also significantly reversed by low-dose hydralazine. Obese mice demonstrated increased markers of kidney fibrosis, inflammation and oxidative stress, but these markers were not significantly improved by hydralazine. CONCLUSION: Low-dose hydralazine ameliorated HFD-induced albuminuria and glomerulosclerosis, independent of alterations in biometric and metabolic parameters or blood pressure regulation. Although the precise mechanism of renoprotection in obesity is unclear, an epigenetic basis may be implicated. These data support repurposing hydralazine as a novel therapy to prevent CKD progression in obese patients. This article is protected by copyright. All rights reserved

Oxidative stress, mitochondrial perturbations and fetal programming of renal disease induced by maternal smoking

© 2015 Elsevier Ltd. An adverse in-utero environment is increasingly recognized to predispose to chronic disease in adulthood. Maternal smoking remains the most common modifiable adverse in-utero exposure leading to low birth weight, which is strongly associated with chronic kidney disease (CKD) in later life. In order to investigate underlying mechanisms for such susceptibility, female Balb/c mice were sham or cigarette smoke-exposed (SE) for 6 weeks before mating, throughout gestation and lactation. Offspring kidneys were examined for oxidative stress, expression of mitochondrial proteins, mitochondrial structure as well as renal functional parameters on postnatal day 1, day 20 (weaning) and week 13 (adult age). From birth throughout adulthood, SE offspring had increased renal levels of mitochondrial-derived reactive oxygen species (ROS), which left a footprint on DNA with increased 8-hydroxydeoxyguanosin (8-OHdG) in kidney tubular cells. Mitochondrial structural abnormalities were seen in SE kidneys at day 1 and week 13 along with a reduction in oxidative phosphorylation (OXPHOS) proteins and activity of mitochondrial antioxidant Manganese superoxide dismutase (MnSOD). Smoke exposure also resulted in increased mitochondrial DNA copy number (day 1-week 13) and lysosome density (day 1 and week 13). The appearance of mitochondrial defects preceded the onset of albuminuria at week 13. Thus, mitochondrial damage caused by maternal smoking may play an important role in development of CKD at adult life

L-carnitine reverses maternal cigarette smoke exposure-induced renal oxidative stress and mitochondrial dysfunction in mouse offspring

© 2015 the American Physiological Society. Maternal smoking is associated with metabolic disorders, renal underdevelopment, and a predisposition to chronic kidney disease in offspring, yet the underlying mechanisms are unclear. By exposing female Balb/c mice to cigarette smoke for 6 wk premating and during gestation and lactation, we showed that maternal smoke exposure induced glucose intolerance, renal underdevelopment, inflammation, and albuminuria in male offspring. This was associated with increased renal oxidative stress and mitochondrial dysfunction at birth and in adulthood. Importantly, we demonstrated that dietary supplementation of L-carnitine, an amino acid shown to increase antioxidant defenses and mitochondrial function in numerous diseases, in smoke-exposed mothers during pregnancy and lactation significantly reversed the detrimental maternal impacts on kidney pathology in these male offspring. It increased SOD2 and glutathione peroxidase 1, reduced ROS accumulation, and normalized levels of mitochondrial preprotein translocases of the outer membrane, and oxidative phosphorylation complexes I–V in the kidneys of mouse progeny after intrauterine cigarette smoke exposure. These findings support the hypothesis that oxidative stress and mitochondrial dysfunction are closely linked to the adverse effects of maternal smoking on male offspring renal pathology. The results of our study suggest that L-carnitine administration in cigarette smokeexposed mothers mitigates these deleterious renal consequence

Impact of maternal e-cigarette vapor exposure on renal health in the offspring

© 2019 New York Academy of Sciences. Maternal smoking during pregnancy is a significant risk factor of renal pathology in the offspring. E-cigarettes are perceived to be a safe option and are increasingly used by pregnant women either continuously during pregnancy or as a replacement for tobacco cigarettes. This study aimed to determine the effects of replacing tobacco cigarettes with e-cigarettes during pregnancy, and continuous e-cigarette use during pregnancy on the offspring's kidneys. Female Balb/c mice were exposed to either air (sham) or tobacco cigarette smoke (SE) for 6 weeks prior to mating, during gestation and lactation. A subset of the “SE group” received e-cigarette vapor (containing nicotine) after mating until pups weaned. Additional female mice were continuously exposed to e-vapor (either with or without nicotine) for 6 weeks prior to mating until pups weaned. Kidneys and urine from the male offspring were assessed at postnatal day 1, day 20 (weaning), and 13 weeks of age (adulthood). E-cigarette replacement was less detrimental to renal development and albuminuria than continuous SE during pregnancy. However, continuous e-vapor exposure during pregnancy increased markers of oxidative stress, inflammation, and fibrosis in the adult offspring, independent of nicotine. E-cigarette use during pregnancy confers future risk to the offspring's kidneys