KMID : 0358320120530010044
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Korean Journal of Urology 2012 Volume.53 No. 1 p.44 ~ p.49
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Activin Receptor-Like Kinase 5 Inhibitor Attenuates Fibrosis in Fibroblasts Derived from Peyronie¡¯s Plaque
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Jang Jin-Hyuk
Ryu Ji-Kan Suh Jun-Kyu
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Abstract
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Purpose: Transforming growth factor-¥â1 (TGF-¥â1) is the key fibrogenic cytokine associated with Peyronie¡¯s disease (PD). The aim of this study was to determine the antifibrotic effect of 3-((5-(6-Methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl) methyl)benzamide (IN-1130), a small-molecule inhibitor of the TGF-¥â type I receptor activin receptor-like kinase 5 (ALK5), in fibroblasts isolated from human PD plaque.
Materials and Methods: Plaque tissue from a patient with PD was used for primary fibroblast culture, and we then characterized primary cultured cells. Fibroblasts were pretreated with IN-1130 (10 ¥ìM) and then stimulated with TGF-¥â1 protein (10 ng/ml). We determined the inhibitory effect of IN-1130 on TGF-¥â1-induced phosphorylation of Smad2 and Smad3 or the nuclear translocation of Smad proteins in fibroblasts. Western blot analyses for plasminogen activator inhibitor-1, fibronectin, collagen I, and collagen IV were performed to evaluate effect of IN-1130 on the production of extracellular matrix proteins.
Results: The treatment of fibroblasts with TGF-¥â1 significantly increased phosphorylation of Smad2 and Smad3 and induced translocation of Smad proteins from the cytoplasm to the nucleus. Pretreatment with IN-1130 substantially inhibited TGF-¥â1-induced phosphorylation of Smad2 and Smad3 and nuclear accumulation of Smad proteins. The TGF-¥â1-induced production of extracellular matrix proteins was also significantly inhibited by treatment with IN-1130 and returned to basal levels.
Conclusions: Overexpression of TGF-¥â and activation of Smad transcriptional factors are known to play a crucial role in the pathogenesis of PD. Thus, inhibition of the TGF-¥â signaling pathway by ALK5 inhibitor may represent a promising therapeutic strategy for treating PD.
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KEYWORD
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Cells, cultured, Penile induration, TGF-beta type I receptor, Transforming growth factor beta
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