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Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts

Stephen Zafiriou^*, Scott R. Stanners^*, Sonia Saad^*, Tania S. Polhill^*, Philip Poronnik and Carol A. Pollock^*

^* Department of Medicine, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia

Address correspondence to: Prof. Carol A. Pollock, Kolling Institute, Department of Medicine, Level 3, Wallace Freeborn Professorial Block, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065, Australia. Phone: 61-2-9926-7126; Fax: 61-2-9436-3719; E-mail: carpol{at}med.usyd.edu.au

Peroxisome proliferator–activated receptor- (PPAR-) 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- 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-1. A reduction in ECM production was similarly observed when CF were exposed to a selective PPAR- agonist (L-805645) in concentrations that caused no toxicity, confirming the antifibrotic effects of pioglitazone were mediated through a PPAR-–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-1. These studies suggest that the PPAR- agonists may have a specific role in ameliorating the course of progressive tubulointerstitial fibrosis under both normoglycemic and hyperglycemic states.

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