Perspectives in Basic Science
Kidney International (2001) 60, 14–30; doi:10.1046/j.1523-1755.2001.00766.x
Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease
YouFei Guan and Matthew D Breyer
Division of Nephrology, and Departments of Molecular Physiology and Biophysics, Veterans Administration Medical Center, and Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Correspondence: YouFei Guan, M.D., Ph.D., Division of Nephrology, S-3223 MCN, Vanderbilt University Medical Center, Nashville, Tennessee 37232–2372, USA. E-mail: youfei.guan@mcmail.vanderbilt.edu
Received 11 August 2000; Revised 14 November 2000; Re-revised 26 2001; Accepted 22 November 2000.
Abstract
Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease. 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 PPAR
, PPAR
and PPAR
, have been cloned and are differentially expressed in several tissues including the kidney. PPAR primary regulates lipid metabolism and modulates inflammation. PPAR is the molecular target of the hypolipidemic fibrates including bezafibrate and clofibrate. PPAR participates in embryonic development, implantation and bone formation. PPAR 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 PPAR, 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. PPAR is predominantly expressed in proximal tubules and medullary thick ascending limbs, while PPAR is expressed in medullary collecting ducts, pelvic urothelium and glomerular mesangial cells. PPAR 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.
Keywords:
fibrate, thiazolidinedione, lipid metabolism, adipogenesis, atherosclerosis, diabetes, hypertension, kidney disease
Abbreviations:
ACO, acyl CoA oxidase; ACS, acyl CoA synthase; AF1, activation function 1; ALBP, adipocyte lipid-binding protein; AP-1, activator protein-1; aP2, adipocyte fatty acid-binding protein; APC, adenomatous polyposis coli; apo, apolipoprotein; ATP, adenosine 5'-triphosphate; BAT, brown adipose tissue; BMI, body mass index; CAP, c-Cbl-associated protein; C/EBPs, CAAT/enhancer binding proteins; COX, cyclooxygenase; CYP4a, cytochrome P450 4A; DBD, DNA binding domain; EPA, eicosapentenoic acid; ES, embryonic stem; FAP, familial adenomatous polyposis coli; FAT, fatty acid translocase; FATP, fatty acid transport protein; FFA, free fatty acid; GLUT4, insulin-dependent glucose transporter; HD, enoyl-CoA hydratase/dehydrogenase multifunctional enzyme; HDL, high-density lipoprotein; 9-HODE and 13-HODE, 9-hydroxy and 13-hydroxy octadecadienoic acids; IL, interleukin; LBD, ligand-binding domain; LCAD, long-chain acyl CoA dehydrogenase; LDL, low-density lipoprotein; L-FABP, hepatic cytosolic fatty acid binding protein; LPL, lipoprotein lipase; LTB4, leukotriene B4; MAP, mitogen-activated protein; MCAD, medium-chain acyl CoA dehydrogenase; ME, malic enzyme; mFABP, muscle fatty acid binding protein; mHMG-CoAS, mitochondrial hydroxymethylglutaryl-CoA synthase; NF-
B, nuclear factor-B; NSAID, nonsteroidal antiinflammatory drug; OxLDL, oxidized low-density lipoprotein; PGD2, prostaglandin D2; PPARs, peroxisome proliferator-activated receptors; PPRE, peroxisome proliferator response element; SREBPs, sterol regulatory element binding proteins; TGF-, transforming growth factor-; TNF-, tumor necrosis factor-; TZDs, thiazolidinediones; UCP, uncoupling proteins; VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cell; WHHL, Watanabe heritable hyperlipidemia
