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.

Public Health Relevance

Prepubertal-childhood obesity and renal disease have become serious public health problems in the United States, but the consequences of prepubertal-childhood obesity on the development of renal disease has not been thoroughly studied. In the current proposal, we will use our model of prepubertal-childhood obesity to explore several mechanisms that may contribute to the early development of renal disease. The data from these studies should provide the scientific community with information critical to develop new treatments or drugs for the prevention of renal disease associated with prepubertal childhood obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109133-04
Application #
9918350
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2017-06-13
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Cunningham Jr, Mark W; Castillo, Javier; Ibrahim, Tarek et al. (2018) AT1-AA (Angiotensin II Type 1 Receptor Agonistic Autoantibody) Blockade Prevents Preeclamptic Symptoms in Placental Ischemic Rats. Hypertension 71:886-893