Thiazolidinediones inhibit albumin uptake by proximal tubular cells through a mechanism independent of peroxisome proliferator activated receptor gamma

Background. Peroxisome proliferator activated receptor gamma (PPAR-gamma) is a ligand-activated transcriptional factor which exerts multiple effects on target cell function. A variety of PPAR-gamma 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 PPAR-gamma ligand 15d-PGJ(2) had no effect on albumin uptake. In cells overexpressing PPAR-gamma or treated with the PPAR-gamma 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 PPAR-gamma. 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. Copyright (C) 2006 S. Karger AG, Basel.