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

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. PPARs play an important role in the general transcriptional control of numerous cellular processes, including lipid metabolism, glucose homeostasis, cell cycle progression, cell differentiation, inflammation and extracellular matrix remodeling. Three PPAR isoforms, designated PPARα, PPARβ and PPARγ, have been cloned and are differentially expressed in several tissues including the kidney. PPARα primary regulates lipid metabolism and modulates inflammation. PPARα is the molecular target of the hypolipidemic fibrates including bezafibrate and clofibrate. PPARβ participates in embryonic development, implantation and bone formation. PPARγ 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 rosiglitazone are specific ligands of PPARγ, and this interaction is responsible for the insulin-sensitizing and hypoglycemic effect of these drugs. The kidney has been shown to differentially express all PPAR isoforms. PPARα is predominantly expressed in proximal tubules and medullary thick ascending limbs, while PPARγ is expressed in medullary collecting ducts, pelvic urothelium and glomerular mesangial cells. PPARβ is ubiquitously expressed at low levels in all segments of nephron. Accumulating data has begun 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 diabetic nephropathy.