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  • Title: Antifibrotic effects of pirfenidone in rat proximal tubular epithelial cells.
    Author: Takakura K, Tahara A, Sanagi M, Itoh H, Tomura Y.
    Journal: Ren Fail; 2012; 34(10):1309-16. PubMed ID: 23002925.
    Abstract:
    OBJECTIVE: Renal fibrosis is a common cause of renal dysfunction with chronic kidney disease. We previously investigated the renoprotective effects of the antifibrotic agent pirfenidone in a rat model of subtotal nephrectomy. Here, we further evaluated the antifibrotic effects of pirfenidone in rat proximal tubular epithelial cells. METHODS: NRK52E cells were incubated in a medium containing either transforming growth factor (TGF)-β1 (3 ng/mL) or platelet-derived growth factor (PDGF)-BB (5 Ang/mL) or both, with or without pirfenidone (0.1-1 mmol/L), for 24 h to assess mRNA expression, for 48 h to assess protein production, and for 1 h or various time (5-120 min) to assess phosphorylation of signal kinase. RESULTS: TGF-β1, a key mediator in renal fibrosis, induced increases in the mRNA expression of various profibrotic factors and extracellular matrix, including plasminogen activator inhibitor type 1 (PAI-1), fibronectin, type 1 collagen, and connective tissue growth factor (CTGF)-increases which pirfenidone significantly inhibited. Specifically, pirfenidone potently inhibited TGF-β1-induced increases in the mRNA expression and protein secretion of PAI-1, an effect mediated, at least in part, via the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Further, PDGF-BB, which has been implicated in renal interstitial fibrosis, potently activated PAI-1 expression under TGF-β1 stimulation, and pirfenidone significantly inhibited TGF-β1- and PDGF-BB-induced increases in PAI-1 expression. CONCLUSIONS: Taken together, these results suggest that TGF-β1 closely correlates with renal fibrosis in cooperation with several fibrosis-promoting molecules, such as PAI-1 and PDGF, in rat proximal tubular epithelial cells, and pirfenidone inhibits TGF-β1-induced fibrosis cascade and will therefore likely exert antifibrotic effects under pathological conditions.
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