Thiazolidinediones Inhibit Albumin Uptake by Proximal Tubular Cells through a Mechanism Independent of Peroxisome Proliferator Activated Receptor Gamma

Abstract

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.