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

Zafiriou, Stephen, Stanners, Scott R., Saad, Sonia, Polhill, Tania S., Poronnik, Phillip and Pollock, Carol A. (2005) Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. Journal of The American Society of Nephrology, 16 3: 638-645. doi:10.1681/ASN.2004040278

Author Zafiriou, Stephen
Stanners, Scott R.
Saad, Sonia
Polhill, Tania S.
Poronnik, Phillip
Pollock, Carol A.
Title Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts
Journal name Journal of The American Society of Nephrology   Check publisher's open access policy
ISSN 1046-6673
Publication date 2005-01-01
Sub-type Article (original research)
DOI 10.1681/ASN.2004040278
Open Access Status Not Open Access
Volume 16
Issue 3
Start page 638
End page 645
Total pages 8
Editor William G. Couser
Allison A. Eddy
Place of publication Washington
Publisher American Society of Nephrology
Language eng
Subject C1
270104 Membrane Biology
320602 Cell Physiology
780105 Biological sciences
730115 Urogenital system and disorders
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 muM 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 muM) and by L-805645. In summary, exposure of human CIF 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.
Keyword Urology & Nephrology
Activated Receptor-gamma
Tissue Distribution
Mesangial Cells
High Glucose
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes DOI: 10.1681/ASN.2004040278

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