Currently, 25% of the U.S population suffers from metabolic syndrome (MetS) which is a condition defined by the presence of at least 3 of these criteria: central obesity, hypertriglyceridemia, low HDL, diabetes and hypertension. The incidence of MetS has paralleled the increasing rate of renal disease. Renal disease associated with MetS can occur before the onset of hypertension or diabetes. Consequently, available treatment options for MetS are only partially effective in preventing or delaying the progression of renal disease. Other studies have revealed obese and/or MetS patients with chronic kidney disease (CKD) present with elevated levels of endothelin-1 (ET-1). However, the role of ET-1 in the progression of renal disease associated with MetS remains unclear. For these reasons, there is a critical need to identify the early mechanisms by which MetS triggers the development of CKD so that more effective treatment strategies can be developed. Recently, we characterized a rodent model of MetS that develops progressive renal injury including renal lipid accumulation without developing overt diabetes and hypertension (SSLepR-/- strain). In the current proposal, we will use this model to determine these underlying mechanisms. Our preliminary data suggest ET-1 production is associated with the early development of proteinuria and changes in renal hemodynamics that may contribute to the early renal injury seen in these rats. Therefore, the central hypothesis of this proposal is that altered renal hemodynamics is an early event occurring in MetS that stimulates glomerular ET-1 production leading to increase podocyte lipid accumulation via the ETA receptor thus facilitating chronic inflammation resulting in podocyte damage, proteinuria, glomerulosclerosis and CKD. We test the central hypothesis in three specific aims:
Aim 1 will investigate whether increases in mechanical strain directly stimulates ET-1 production and contributes to podocyte injury, Aim 2 determine that increased lipid accumulation in podocytes is mediated by the ETA receptor, and Aim 3 to test the effects chronic blockade of the ET- 1/ETA cascade in delayig the development of renal injury and prevent renal lipid accumulation in the SSLepR-/- strain. This proposal will use a combination of novel in vivo and in vitro experimental techniques to determine whether ET-1 participates in renal lipid accumulation during the development of renal disease associated with MetS.

Public Health Relevance

Obesity-metabolic syndrome (MetS) is a major health problem in the United States. MetS includes a cluster of metabolic abnormalities such as diabetes, hypertension, obesity and dyslipidemia that increase the risk for cardiovascular disease and chronic kidney disease (CKD). In the current proposal, we will use our model of MetS to explore several mechanisms that may contribute to the early development of renal disease in the absence of overt diabetes and hypertension in order to provide the scientific community with information that can be used to identify novel treatments and drugs for the prevention of renal disease associated with MetS.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1)
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Rankin, Tracy L
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University of Mississippi Medical Center
Schools of Medicine
United States
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