Background: Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor which exerts multiple effects on target cell function. A variety of PPARγ ligands are known, including the antidiabetic thiazolidinediones (TZDs). There is evidence that suggests that these drugs may improve metabolic parameters, proteinuria, and blood pressure in type 2 diabetes. Method: We investigated the potentially beneficial effects of TZDs in opossum kidney proximal tubular cells, focussing particularly on protein handling. Results: Three TZDs, ciglitazone, rosiglitazone, and troglitazone, all inhibited FITC-albumin uptake by cells in a dose-dependent manner in the absence of cell cytotoxicity or effects on binding. In contrast, the structurally unrelated PPARγ ligand 15d-PGJ2 had no effect on albumin uptake. In cells overexpressing PPARγ or treated with the PPARγ antagonist GW9662, no alterations in the inhibitory effects of TZDs were observed. All TZDs reduced cholesterol synthesis, and supplementation of cells with non-sterol precursors of cholesterol, mevalonate, farnesol, and geranylgeranyl pyrophosphate, reversed the effects of TZDs. Conclusions: TZDs inhibit albumin uptake and cholesterol synthesis in proximal tubular cells independently of PPARγ. Depletion of cholesterol precursors by TZDs is at least partially responsible for reduced albumin uptake. These results support a new role for TZDs to combat progressive proteinuric renal disease.

Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmery U, Mangelsdorf DJ, Umesono K, Evans RM: Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 1994;91:7355–7359.
Yang T, Michele DE, Park J, Smart AM, Lin Z, Brosius FC III, Schnermann JB, Briggs JP: Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. Am J Physiol 1999;277:F966–F973.
Schoonis K, Staels B, Auwerx J: The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996;1302:93–109.
Desvergne B, Wahli W: Peroxisome proliferator activated receptors: nuclear control of metabolism. Endocr Rev 1999;20:640–688.
Kersten S, Desvergen BW, Wahli W: Role of PPARs in health and disease. Nature 2000;405:421–424.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky JM: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–1193.
Rangwala SM, Lazar MA: Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 2004;25:331–336.
Imano E, Kanda T, Nakatani Y, Nishida T, Arai K, Motomura M, Kajimato Y, Yamasaki Y, Hori M: Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 1998;21:2135–2139.
Asano T, Wakisaka M, Yoshinari M, Iino K, Sonoki K, Iwase M, Fujishima M: Peroxisome proliferator-activated receptor gamma 1 (PPARgamma 1) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation. Biochim Biophys Acta 2000;1497:148–154.
McCarthy KJ, Routh RE, Shaw W, Walsh K, Welbourne TC, Johnson JH: Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion. Kidney Int 2000;58:2341–2350.
Ma LJ, Marcantoni C, Linton MF, Fazio S, Fogo A: Peroxisome proliferator activated receptor-γ agonist troglitazone protects against non-diabetic glomerulsclerosis in rats. Kidney Int 2001;59:1899–1910.
Ghosh SS, Gehr TW, Ghosh S, Fakhry I, Sica DA, Lyall V, Schoolwerth AC: PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase. Kidney Int 2003;64:52–62.
Zafiriou S, Stanners SR, Saad S, Polhill TS, Poronnik P, Pollock CA: Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol 2005;16:638–645.
Chana RS, Lewington AJ, Brunskill NJ: Differential effects of peroxisome proliferator activated receptor-γ (PPARγ) ligands in proximal tubular cells: thiazolidinediones are partial PPARγ agonists. Kidney Int 2004;65:2081–2090.
Arici M, Chana R, Lewington A, Brown J, Brunskill NJ: Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol 2003;14:17–27.
Wang M, Wise SC, Leff T, Su TZ: Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-γ. Diabetes 1999;48:254–260.
Cominacini L, Garbin U, Pastorino AM, Campagnola M, Fratta Pasini A, Davoli A, Rigoni A, Lo Cascio V: Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells. Diabetologia 1997;40:165–172.
Fulgencio JP, Khol C, Girard J, Pegorier JP: Troglitazone inhibits fatty acid oxidation and esterification and gluconeogenesis in isolated hepatocytes from starved rats. Diabetes 1996;45:1556–1562.
Brunskill NJ: Albumin signals the coming of age of proteinuric nephropathy. J Am Soc Nephrol 2004;15:504–505.
Remuzzi G: The nephropathic nature of proteinuria. Curr Opin Nephrol Hypertens 1999;8:655–663.
Sidaway JE, Davidson RG, McTaggart F, Orton TC, Scott RC, Smith GJ, Brunskill NJ: Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells. J Am Soc Nephrol 2004;15:2258–2265.
Abbate M, Zoja C, Capitanio M, Remuzzi G: In progressive nephropathies overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. J Am Soc Nephrol 1998;9:1213–1224.
Gekle M: Renal tubule albumin transport. Annu Rev Physiol 2005;67:573–594.
Brunskill NJ, Stuart J, Tobin A, Walls J, Nahorski S: Receptor-mediated endocytosis of albumin by kidney proximal tubule cells is regulated by phosphatidylinositide 3-kinase. J Clin Invest 1998;101:2140–2150.
Sinensky M: Recent advances in the study of prenylated proteins. Biochim Biophys Acta 2000;1484:93–106.
Lamaze C, Chuang TH, Terlecky LJ, Bokoch GM, Schmid SL: Regulation of receptor-mediated endocytosis by Rho and Rac. Nature 1996;382:177–179.
Guo Q, Sahoo SP, Wang PR, Milot DP, Ippolito MC, Wu MS, Baffic J, Biswas C, Hernandez M, Lam MH, Sharma N, Han W, Kelly LJ, MacNaul KL, Zhou G, Desai R, Heck JV, Doebber TW, Berger JP, Moller DE, Sparrow CP, Chao YS, Wright SD: A novel peroxisome proliferator-activated receptor α/γ dual agonist demonstrates favorable effects on lipid homeostasis. Endocrinology 2004;145:1640–1648.
Iida KT, Kawakami Y, Suzuki H, Sone H, Shimano H, Toyoshima H, Okuda Y, Yamada N: PPARγ ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages. FEBS Lett 2002;520:177–181.
Zafiriou S, Stanners SC, Polhill TS, Porronik P, Pollock CA: Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses. Kidney Int 2004;65:1647–1653.
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