Aim: To determine whether maternal obesity accelerates the development of chronic kidney disease (CKD) in offspring with diabetes.

Background: We have previously shown that maternal obesity is associated with adverse renal outcomes in offspring at an early time point. We hypothesised that a second-hit such as diabetes may further exacerbate renal damage in offspring exposed to maternal obesity. 

Methods: Female C57Bl6 mice were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and weaning, and their offspring were weaned to chow diet. At Week 8, the male offspring were randomized to streptozotocin 55mg/kg/day for five consecutive days (to induce type 1 diabetes), strepotozotocin 100 mg once only (to induce type 2 diabetes) or placebo. Weight and glucose levels were tested fortnightly. 24 h urine collection was performed at Week 20 and 30. The kidneys were harvested at Week 32 and renal structure was observed. Gene expression levels of proinflammatory, oxidative stress and profibrotic markers were measured by real time PCR and confirmed with western blot and/or immunohistochemistry.

Results: Offspring of obese mothers had increased epididymal and retroperitoneal fat deposition. Diabetic offspring had reduced weight gain, hyperglycaemia, glycosuria and microalbuminuria. Urinary albumin measurements were highest in diabetic offspring of obese mothers. Furthermore, the kidneys of the offspring exposed to maternal obesity and induced with diabetes had increased structural damage, heightened inflammatory changes and greater levels of oxidative stress markers when compared to the kidneys of diabetic offspring of normal weight mothers. There was also evidence of renal fibrosis.

Conclusions: Offspring exposure to maternal obesity accelerates the severity of damage to the kidney caused by diabetes.  Renal inflammation and oxidative stress may be key pathways for this accelerated risk. Thus, maternal weight in pregnancy is an important modifiable risk factor for CKD in offspring.