Role of FXR in Renal Disease of Metabolic Syndrome and Aging

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DESCRIPTION (provided by applicant): Obesity, insulin resistance, diabetes mellitus, and aging are the leading causes of renal and cardiovascular disease. In addition to the important roles played by hypertension, abnormal carbohydrate metabolism, profibrotic growth factors, proinflammatory cytokines, oxidative stress, and advanced glycation end products, abnormal lipid metabolism and accumulation of lipids also play an important role in the pathogenesis of obesity, age, and diabetes-related renal disease. In a) C57BI/6 mice with diet induced obesity and insulin resistance, and b) aging mice and rats, we have found increased renal expression of the nuclear transcriptional factors: I) the sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), and II) the carbohydrate response element binding protein (ChREBP), which result in increased synthesis and accumulation of triglyceride and cholesterol and correlate with manifestations of obesity and diabetes related renal sclerosis and proteinuria. Recent studies indicate that the farnesoid X receptor (FXR) plays an important role in lipid metabolism through modulation of SREBP-1 and ChREBP. FXR also has antiinflammatory and antifibrotic effects. FXR is highly expressed in the kidney and we have found that its expression and their target enzymes are altered in the kidneys of mice with diet induced obesity and insulin resistance and in aging mice. However the potential role of FXR in preventing renal disease is not known. Our hypotheses are: 1) FXR plays an important role in regulation of renal disease through modulation of renal lipid and carbohydrate metabolism, fibrosis, inflammation, and oxidative stress; 2) Treatment with FXR agonists will attenuate obesity and age-related renal disease. Our aims are: 1) To determine the role of FXR ligands in modulation of a) renal disease, b) renal lipid metabolism, c) fibrosis, d) inflammation, and e) oxidative stress in I) mice with diet induced obesity and insulin resistance and II) aging mice; 2) To determine the direct role of FXR in modulation of renal glomerular podocyte response to fatty acids, glucose and insulin, including apoptosis, lipid metabolism, fibrosis, inflammation, and oxidative stress;3) To determine if conditional and inducible a) FXR overexpression in podocytes will significantly attenuate, and alternatively if b) FXR knockout in podocytes will significantly accelerate obesity and insulin resistance or age-related renal disease.