Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring

Abstract

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.

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

“…Several factors have been shown to contribute to the progression of diabetic nephropathy; hyperglycemia, hypertension, obesity and advancing age have been extensively characterized (2,3). However, the precise mechanism for this condition remains unclear.…”

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

“…Additionally, maternal obesity increases the offspring's risk of dysglycemia, diabetes, and hypertension, which may propagate renal dysfunction in later life (4). We demonstrated that the offspring of obese dams have increased renal damage, including renal fibrosis, inflammation, and oxidative stress changes (29). Compared to the offspring of lean mice, we observed significantly worse renal function and albuminuria in the offspring of obese dams.…”

“…Compared to the offspring of lean mice, we observed significantly worse renal function and albuminuria in the offspring of obese dams. While this effect occurred independently of the development of diabetes, renal function and urinary albumin excretion were significantly exacerbated when the offspring also developed diabetes (29). Epidemiologic data in humans support the association of maternal obesity with the development of CKD in the offspring, although data are limited.…”

“…We and others have proposed several possible mechanisms by which maternal obesity programs metabolic syndrome and CKD in offspring. These include upregulation of inflammatory, oxidative stress and lipid pathways, mitochondrial stress and alterations in the renin-angiotensin system, renal sympathetic nervous activity, and increased sodium reabsorption (20,21,23,27,29,31,32). In rodent models, we have previously identified increased levels of renal oxidative stress in the offspring of obese mothers.…”

Maternal obesity and offspring risk of chronic kidney disease

“…Utilizing the same rodent model of maternal obesity, we then showed similar metabolic changes and kidney histological features in male offspring from obese mother at postnatal week 32, especially in the offspring exposed to diet‐induced obesity (HFD‐feeding throughout adulthood) and streptozotocin‐induced diabetes . We found offspring from obese mother had impaired glucose tolerance, higher retroperitoneal and epididymal fat depositions ( P < 0.01 vs control) despite similar body weight, alongside higher serum creatinine levels, 24 h urinary albumin creatinine ratio, worse renal tubular injury and glomerulosclerosis scores when compared to offspring from lean mothers . These findings suggest maternal obesity has significant adverse effects on the offspring’s kidneys across the lifespan, from early in postnatal life (days 1 and 20), persistent to middle adulthood (week 32).…”