Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts

Zafiriou, S, Stanners, S, Saad, S, Polhill, T, Poronnik, P and Pollock, C 2005, 'Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts', Journal of the American Society of Nephrology, vol. 16, no. 3, pp. 638-645.

Document type: Journal Article
Collection: Journal Articles

Title Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts
Author(s) Zafiriou, S
Stanners, S
Saad, S
Polhill, T
Poronnik, P
Pollock, C
Year 2005
Journal name Journal of the American Society of Nephrology
Volume number 16
Issue number 3
Start page 638
End page 645
Total pages 8
Publisher American Society of Nephrology
Abstract Peroxisome proliferator-activated receptor-Gamma (PPAR-Gamma) agonists are increasingly used in patients with diabetes, and small studies have suggested a beneficial effect on renal function, but their effects on extracellular matrix (ECM) turnover are unknown. The aims of this study were to investigate the effects of the PPAR-Gamma agonist pioglitazone on growth and matrix production in human cortical fibroblasts (CF). Cell growth and ECM production and turnover were measured in human CF in the presence and absence of 1 and 3 μM pioglitazone. Exposure of CF to pioglitazone caused an antiproliferative (P < 0.0001) and hypertrophic (P < 0.0001) effect; reduced type IV collagen secretion (P < 0.01), fibronectin secretion (P < 0.0001), and proline incorporation (P < 0.0001); decreased MMP-9 activity (P < 0.05); and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 secretion (P < 0.001 and P < 0.0001, respectively). These effects were independent of TGF-Beta1. A reduction in ECM production was similarly observed when CF were exposed to a selective PPAR-Gamma agonist (L-805645) in concentrations that caused no toxicity, confirming the antifibrotic effects of pioglitazone were mediated through a PPAR-Gamma-dependent mechanism. Exposure of CF to high glucose conditions induced an increase in the expression of collagen IV (P < 0.05), which was reversed both in the presence of pioglitazone (1 and 3 μM) and by L-805645. In summary, exposure of human CF to pioglitazone causes an antiproliferative effect and reduces ECM production through mechanisms that include reducing TIMP activity, independent of TGF-Beta1. These studies suggest that the PPAR-Gamma agonists may have a specific role in ameliorating the course of progressive tubulointerstitial fibrosis under both normoglycemic and hyperglycemic states.
Subject Basic Pharmacology
DOI - identifier 10.1681/ASN.2004040278
Copyright notice Copyright © 2005 by the American Society of Nephrology.
ISSN 1046-6673
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