Thiazolidinediones inhibit albumin uptake by proximal tubular cells through a mechanism independent of peroxisome proliferator activated receptor gamma.
BACKGROUND
Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand-activated transcriptional factor which exerts multiple effects on target cell function. A variety of PPARgamma 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.


METHODS
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 PPARgamma ligand 15d-PGJ2 had no effect on albumin uptake. In cells overexpressing PPARgamma or treated with the PPARgamma 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 PPARgamma. 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.
Chana
Ravinder S
RS
Department of Infection, Immunity and Inflammation, Faculty of Medicine and Biological Sciences, University of Leicester, UK.
Brunskill
Nigel J
NJ
D000418:Albumins / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D002839:Chromans / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008024:Ligands; D008798:Mevalonic Acid / Q000494:pharmacology; D009893:Opossums; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D053778:Thiazolidines; D000077288:Troglitazone
C457499:2-chloro-5-nitrobenzanilide; D000418:Albumins; D000813:Anilides; D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D011106:Polyisoprenyl Phosphates; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D000077154:Rosiglitazone; D005204:Farnesol; C033089:thiazoline-2-thione; D002784:Cholesterol; D000077288:Troglitazone; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; C039671:ciglitazone