Pleiotropic Actions of Ppar Agonist:A Potential Therapeutic Perspectives in the Treatment of Diabetic Nephropathy

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARα activators reduce the quantities of available fatty acids for triglyceride-rich very low-density lipoprotein synthesis in the liver. PPARα binds to a diverse set of ligands, namely, arachidonic acid metabolites (prostaglandins and leukotrienes), plasticizers and synthetic fibrate drugs such as bezafibrate, fenofibrate, clofibrate, and gemfibrozil. PPARγ agonists may also have therapeutic utility in the treatment of other conditions such as atherosclerosis, inflammation, cancer, and diabetic nephropathy. PPARδ plays a role in lipid metabolism, cholesterol efflux, and adipogenesis. In particular, diabetes is associated with the activation of enzymes that directly liberate ROS, including NAD(P)H oxidase. PPARα is expressed in proximal tubules and medullary thick ascending limbs where it is thought to be involved in the regulation of protein-degradation systems through maintenance of ATP homeostasis, control of fatty acid β-oxidation, and regulation of cytochrome P450 in proximal tubules. PPARγ is predominantly expressed in medullary collecting ducts and pelvic urothelium, and the latter site is potentially important for the putative link between PPARγ agonists and transitional cell cancer. The third isoform of PPAR and PPARβ/δ is also ubiquitously expressed in the kidney, with the highest levels observed in the proximal straight tubule in renal cortex and medulla. The review focuses on pleiotropic actions of PPAR agonist.