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

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Abstract
Peroxisome proliferator–activated receptor-γ (PPAR-γ) 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-γ 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-β1. A reduction in ECM production was similarly observed when CF were exposed to a selective PPAR-γ agonist (L-805645) in concentrations that caused no toxicity, confirming the antifibrotic effects of pioglitazone were mediated through a PPAR-γ–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-β1. These studies suggest that the PPAR-γ agonists may have a specific role in ameliorating the course of progressive tubulointerstitial fibrosis under both normoglycemic and hyperglycemic states.