Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring

© 2018 The Author(s). Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed

FXR expression is associated with dysregulated glucose and lipid levels in the offspring kidney induced by maternal obesity

© 2015 Glastras et al. Background: Maternal obesity is associated with dysregulation of glucose and lipid metabolism with consequent exposure of the fetus to an abnormal metabolic milieu. It is recognized that maternal obesity predisposes offspring to chronic kidney disease (CKD). We aimed to determine whether the nuclear Farnesoid X receptor (FXR), known to play a role in maintaining homeostasis of glucose and lipid metabolism, is involved in renal injury in offspring of obese mothers. Methods: Maternal obesity was established in a rat model by feeding dams with high-fat diet prior to and during pregnancy and lactation. The offspring's kidneys were examined at postnatal Day 1and Day 20. Human kidney 2 (HK2) cells were exposed to high glucose with or without the FXR agonist GW4064 or when FXR mRNA was silenced. Results: Glucose intolerance in the offspring of obese mothers was evident at weaning, with associated downregulation of renal FXR expression and upregulation of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1). HK2 cells exposed to high glucose had reduced FXR expression and increased MCP-1, TGF-β1, fibronectin and collagen IV expression, which was reversed in the presence of GW4064. FXR-silenced HK2 cells had amplified pro-inflammatory and pro-fibrotic markers under high glucose conditions. Conclusions: Maternal obesity influences renal expression of pro-inflammatory and fibrotic factors that predispose the offspring to CKD. This was associated with the downregulation of the renal FXR expression suggesting a potential protective role for FXR

Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring

Maternal obesity is known to increase the risk of obesity and diabetes in offspring. Though diabetes is a key risk factor for the development of chronic kidney disease (CKD), the relationship between maternal obesity and CKD has not been clearly defined. In this study, a mouse model of maternal obesity was employed to determine the impact of maternal obesity on development of diabetic nephropathy in offspring. Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow diet. At postnatal Week 8, offspring were randomly administered low dose streptozotocin (STZ, 55 mg/kg/day for five days) to induce diabetes. Assessment of renal damage took place at postnatal Week 32. We found that offspring of obese mothers had increased renal fibrosis, inflammation and oxidative stress. Importantly, offspring exposed to maternal obesity had increased susceptibility to renal damage when an additional insult, such as STZ-induced diabetes, was imposed. Specifically, renal inflammation and oxidative stress induced by diabetes was augmented by maternal obesity. Our findings suggest that developmental programming induced by maternal obesity has implications for renal health in offspring. Maternal obesity should be considered a risk factor for CKD

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

Mouse models of diabetes, obesity and related kidney disease

© 2016 Glastras et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice

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

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

Timing of host feeding drives rhythms in parasite replication

Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the hosts' peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the hosts' peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new arena for studying host-parasite-vector coevolution and has broad implications for applied bioscience

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

© 2018 American Society for Biochemistry and Molecular Biology Inc. All rights reserved. Chronic kidney disease (CKD) is a global epidemic, and itsmajor risk factors include obesity and type 2 diabetes. Obesity not only promotes metabolic dysregulation and the development of diabetic kidney disease but alsomay independently lead to CKD by a variety ofmechanisms, including endocrine andmetabolic dysfunction, inflammation, oxidative stress, altered renal hemodynamics, and lipotoxicity. Deleterious renal effects of obesity can also be transmitted from one generation to the next, and it is increasingly recognized that offspring of obese mothers are predisposed to CKD. Epigenetic modifications are changes that regulate gene expression without altering theDNAsequence.Of these,DNAmethylation is the most studied. Epigenetic imprints, particularlyDNA methylation, are laid down during critical periods of fetal development, and they may provide a mechanism by whichmaternal-fetal transmissionof chronic diseaseoccurs.Ourcurrent review explores the evidence for the role of DNAmethylationinthedevelopment ofCKD,diabetickidneydisease,diabetes, andobesity.DNAmethylationhas been implicated in renal fibrosis-the final pathophysiologic pathway in the development of end-stage kidney disease-which supports the notion that demethylating agentsmay play a potential therapeutic role in preventing development and progression of CKD

The Clinical Role of Insulin Degludec/Insulin Aspart in Type 2 Diabetes: An Empirical Perspective from Experience in Australia

Treatment intensification in people with type 2 diabetes following failure of basal insulin commonly involves the addition of a rapid-acting insulin analogue (basal plus one or more prandial doses; multiple daily injections) or by a switch to premixed insulin. Insulin degludec/insulin aspart (IDegAsp), comprising rapid-acting insulin aspart and ultra-long-acting insulin degludec in solution, enables both fasting and post-prandial glucose control, with some advantages over other treatment intensification options. These include straightforward dose titration, flexibility in dose timing, low injection burden, simplicity of switching and a lower risk of hypoglycaemia. In Australia, where insulin degludec on its own is not available, IDegAsp enables patients to still benefit from its ultra-long-acting properties. This review aims to provide guidance on where and how to use IDegAsp. Specifically, guidance is included on the initiation of IDegAsp in insulin-naïve patients, treatment intensification from basal insulin, switching from premixed or basal-bolus insulin to IDegAsp, up-titration from once- to twice-daily IDegAsp and the use of IDegAsp in special populations or situations