Activin Receptor-Like Kinase 5 Inhibitor Attenuates Fibrosis in Fibroblasts Derived from Peyronie's Plaque.
- Author:
Jin Hyuk JANG
1
;
Ji Kan RYU
;
Jun Kyu SUH
Author Information
- Publication Type:Original Article
- Keywords: Cells, cultured; Penile induration; TGF-beta type I receptor; Transforming growth factor beta
- MeSH: Activin Receptors; Activins; Blotting, Western; Cells, Cultured; Collagen; Cytoplasm; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Fibrosis; Humans; Imidazoles; Male; Penile Induration; Phosphorylation; Plasminogen Activators; Protein-Serine-Threonine Kinases; Quinoxalines; Receptors, Transforming Growth Factor beta; Smad Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1
- From:Korean Journal of Urology 2012;53(1):44-49
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Transforming growth factor-beta1 (TGF-beta1) 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-beta 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 microM) and then stimulated with TGF-beta1 protein (10 ng/ml). We determined the inhibitory effect of IN-1130 on TGF-beta1-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-beta1 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-beta1-induced phosphorylation of Smad2 and Smad3 and nuclear accumulation of Smad proteins. The TGF-beta1-induced production of extracellular matrix proteins was also significantly inhibited by treatment with IN-1130 and returned to basal levels. CONCLUSIONS: Overexpression of TGF-beta and activation of Smad transcriptional factors are known to play a crucial role in the pathogenesis of PD. Thus, inhibition of the TGF-beta signaling pathway by ALK5 inhibitor may represent a promising therapeutic strategy for treating PD.
