Mechanisms involved in the early development of renal disease associated with prepubertal obesity

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Project Abstract Prepubertal childhood obesity has emerged as an epidemic and major health problem in the United States. Recent studies suggest that that childhood obesity is associated with increased risk of renal injury in children. Although the link between obesity and the development of type II diabetic nephropathy is well-documented, the consequences of childhood obesity as an independent risk factor in the absence of diabetes in the development of renal disease has received less attention. Currently, there are several obese animal models that develop renal disease, but these models have limited use in the investigation of the early mechanisms responsible for the development of renal injury prior to hypertension, diabetes, and/or puberty. As most of these obese models do not develop progressive proteinuria and chronic kidney disease (CKD). Recently, we observed our obese rat model (prepubertal obese - PPO) develops podocyte injury and 3-fold increase in proteinuria prior to the development of hypertension and diabetes at 6 weeks of age (childhood), which progresses to severe hypertension, CKD by 18 weeks of age (adulthood). In the current proposal, we will use our model of prepubertal obesity to explore several mechanisms that may contribute to the development of renal disease. The proposed studies will test whether glomerular hyperfiltration and lipid accumulation stimulate podocyte injury and macrophage inflitration leading to proteinuria and renal injury during prepubertal obesity. We will compare early changes in glomerular capillary pressure (Pgc) between the PPO model and their control-lean counterparts and determine whether there is a direct effect of mechanical strain/cyclic stretch on lipid accumulation in podocytes isolated from both strains. We also will evaluate the role of macrophages on the early development of proteinuria in the PPO model. These results should provide the scientific community with an obese animal model system that develops proteinuria, prior to puberty, to study mechanisms involved in renal injury and provide information critical to develop new treatments for the prevention of renal disease associated with prepubertal childhood obesity.