Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease

Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targ ets in renal disease. Peroxisome proliferator-activated receptors (PPARs) a re members of the nuclear hormone receptor superfamily of ligand-dependent transcription Factors. PPARs play an important role in the general transcri ptional control of numerous cellular processes, including lipid metabolism. glucose homeostasis, cell cycle progression, cell differentiation, inflamm ation and extracellular matrix remodeling. Three PPAR isoforms, designated PPAR alpha. PPAR beta and PPAR I, have been cloned and are differentially e xpressed in several tissues including the kidney. PPARa primary regulates l ipid metabolism and modulates inflammation. PPAR alpha is the molecular tar get of the hypolipidemic fibrates including bezafibrate and clofibrate. PPA R beta participates in embryonic development, implantation and bone formati on. PPAR gamma is a key factor in adipogenesis and also plays an important role in insulin sensitivity cell cycle regulation and cell differentiation. Antidiabetic thiazolidinediones (TZDs) such as troglitazone and rosiglitaz one are specific ligands of PPAR gamma, and this interaction is responsible for the insulin-sensitizing and hypoglycemic effect of these drugs. The ki dney has been shown to differentially express all PPAR isoforms. PPAR alpha is predominantly expressed in proximal tubules and medullary thick ascendi ng limbs, while PPAR alpha is expressed in medullary collecting ducts. pelv ic urothelium and glomerular mesangial cells. PPAR beta is ubiquitously exp ressed at low levels in all segments of nephron. Accumulating data has begu n to emerge suggesting physiological and pathophysiological roles of PPARs in several tissues including the kidney. The availability of PPAR-selective agonists and antagonists may provide a new approach to modulate the renal response to diseases including glomerulonephritis. glomerulosclerosis and d iabetic nephropathy.