The proxisome proliferator-activated receptor subtype (PPAR) is a multi-functional ligand-activated transcription factor. In addition to the well recognized metabolic action, PPAR exerts a profound influence on fluid metabolism and blood pressure (Bp) control through a complex mechanism involving regulation of renal sodium transport as well as vascular function. Previous studies employing mice with conditional deletion of PPAR in the collecting duct (CD) document a sodium-retaining function of PPAR in the distal nephron that underlies fluid retention and body weight gains associated with thiazolidinediones (TZDs). Further analysis of the KO mice on a low sodium diet reveals new evidence for a physiological function of CD PPAR in regulation of sodium balance and Bp. We propose to investigate specific targets, endogenous ligands and regulatory mechanisms of CD PPAR in the setting of sodium depletion. In particular, we will determine whether the recently discovered endogenous PPAR ligands which are nitrated fatty acids (NO2-FA), including LNO2 and OA-NO2, may play a role in regulation of CD function. Additionally, we will investigate the possible pathological role of CD PPAR in obesity-induced hypertension by testing the hypothesis that CD PPAR may serve as a link between energy metabolism and renal sodium excretion. To resolve the paradox that the activation of CD PPAR leads to fluid retention but is not associated with hypertension, we propose to investigate the potential anti-hypertensive and vasculoprotective functions of PPAR using mice with conditional deletion of PPAR in endothelial cells (EC PPAR KO) and vascular smooth muscle cells (SM PPAR KO). We propose the following three aims: 1) to investigate the role of NO2-FA/PPAR in regulation of renal sodium transport, 2) to investigate the role of NO2-FA/PPAR in regulation of sodium excretion during changing energy balance, and 3) to investigate the vascular function of NO2-FA/PPAR. New information provided by this proposal is expected to offer new insights into the integrative role of NO2-FA/PPAR in the control of renal and vascular functions.
The prevalence of overweight and obesity has dramatically increased during the past 2 decades with 65% of the United States adults being overweight and 31% of adult being obese. Obesity related insulin resistance and hypertension are a major risk factor for cardiovascular diseases. The PPAR activators thiazolidinediones (TZDs) are highly effective for control of type 2 diabetes and also exhibit beneficial effects on cardiovascular disease. The current proposal is expected to provide new information for required for development of more effective therapies for the human disease.
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