Abstract
BackgroundMaternal 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.MethodsFemale 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.ResultsOffspring 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.ConclusionGestational 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.
Highlights
Obesity is a major health problem which predisposes individuals to develop significant consequences, including type 2 diabetes, hypertension, dyslipidaemia, cardiovascular disease, and chronic kidney disease (CKD) (Glastras et al, 2016a)
We have previously shown that maternal obesity causes renal changes in offspring, such as increased albuminuria, renal fibrosis, oxidative stress and inflammation, all of which promote the development and progression of CKD (Glastras et al, 2016c)
Urinary albumin:creatinine ratio (ACR) increased in HH compared to CC (p < 0.0001, Table 3)
Summary
Obesity is a major health problem which predisposes individuals to develop significant consequences, including type 2 diabetes, hypertension, dyslipidaemia, cardiovascular disease, and chronic kidney disease (CKD) (Glastras et al, 2016a). It is increasingly recognized that the detrimental effects of obesity may be transmitted from one generation to the and that maternal obesity has implications for offspring kidney health (Glastras et al, 2018) This phenomenon is in keeping with the theory of the developmental origins of health and disease, which suggests that insults occurring during critical periods of fetal development increase offspring susceptibility to chronic disease later in life (Tain and Hsu, 2017). We have previously shown that maternal obesity causes renal changes in offspring, such as increased albuminuria, renal fibrosis, oxidative stress and inflammation, all of which promote the development and progression of CKD (Glastras et al, 2016c). 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
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