Document Detail


Thiazolidinediones inhibit albumin uptake by proximal tubular cells through a mechanism independent of peroxisome proliferator activated receptor gamma.
MedLine Citation:
PMID:  16508249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. 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 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.
Authors:
Ravinder S Chana; Nigel J Brunskill
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-02-28
Journal Detail:
Title:  American journal of nephrology     Volume:  26     ISSN:  0250-8095     ISO Abbreviation:  Am. J. Nephrol.     Publication Date:  2006  
Date Detail:
Created Date:  2006-04-07     Completed Date:  2006-08-11     Revised Date:  2007-02-14    
Medline Journal Info:
Nlm Unique ID:  8109361     Medline TA:  Am J Nephrol     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  67-74     Citation Subset:  IM    
Copyright Information:
Copyright 2006 S. Karger AG, Basel
Affiliation:
Department of Infection, Immunity and Inflammation, Faculty of Medicine and Biological Sciences, University of Leicester, UK.
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MeSH Terms
Descriptor/Qualifier:
Albumins / metabolism
Anilides / pharmacology
Animals
Cells, Cultured
Cholesterol / biosynthesis
Chromans / pharmacology
Farnesol / pharmacology
Kidney Tubules, Proximal / drug effects*
Ligands
Mevalonic Acid / pharmacology
Opossums
PPAR gamma / antagonists & inhibitors,  physiology*
Polyisoprenyl Phosphates / pharmacology
Thiazoles / pharmacology*
Thiazolidinediones / pharmacology
Thiazolidines
Chemical
Reg. No./Substance:
0/2-chloro-5-nitrobenzanilide; 0/Albumins; 0/Anilides; 0/Chromans; 0/Ligands; 0/PPAR gamma; 0/Polyisoprenyl Phosphates; 0/Thiazoles; 0/Thiazolidinediones; 0/Thiazolidines; 122320-73-4/rosiglitazone; 150-97-0/Mevalonic Acid; 4602-84-0/Farnesol; 5685-05-2/thiazoline-2-thione; 57-88-5/Cholesterol; 6699-20-3/geranylgeranyl pyrophosphate; 74772-77-3/ciglitazone; 97322-87-7/troglitazone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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