Maternal obesity increases the risk of chronic disease in the offspring, including diabetes, hypertension and cardiovascular disease. Developmental programming may also affect offspring’s risk of chronic kidney disease. GLP-1 receptor agonists, such as Exendin-4 are effective blood glucose lowering agents and achieve modest weight loss in the setting of type 2 diabetes. They may also have beneficial effects on the kidney. We hypothesized that administration of Exendin 4 (Exd-4) may reduce inflammation and oxidative stress in the kidneys of offspring of obese mothers.
Method: Female rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation and their offspring were weaned to normal or HFD. The offspring were randomised to Exd-4 or placebo at weaning and their kidneys harvested in early adulthood.
Results: Offspring of obese mothers fed HFD had increased weight and reduced glucose tolerance. Exd-4 significantly ameliorated these effects. The kidneys of offspring of obese mothers, regardless of postnatal diet, had increased markers of inflammation and oxidative stress. By RT-PCR, mRNA expression of inflammatory markers, monocyte chemoattractant protein -1 (MCP-1) and transforming growth factor was significantly increased in offspring of obese mothers regardless of postnatal diet. Increased MCP-1 mRNA expression in offspring of obese mothers fed HFD was ameliorated by Exd-4. Inducible nitric oxide synthase mRNA, a measure of oxidative stress, was increased by maternal obesity with or without HFD consumption in postnatal life and ameliorated by Exd-4 therapy. Superoxide dismutase (SOD) are enzymes with important anti-oxidant and anti-inflammatory effects. Exd-4 increased SOD activity significantly in the offspring of obese mothers fed normal diet.
Conclusion: We conclude that maternal obesity affects inflammatory and oxidative stress pathways within offspring’s kidneys. Exd-4 appears to have a novel protective role against the deleterious renal effects of in utero exposure to maternal obesity.