Activin Receptor-Like Kinase 5 Inhibitor Attenuates Fibrosis in Fibroblasts Derived from Peyronie's Plaque
Korean Journal of Urology
; : 44-49, 2012.
Article
in En
| WPRIM
| ID: wpr-106965
Responsible library:
WPRO
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.
Key words
Full text:
1
Index:
WPRIM
Main subject:
Penile Induration
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Phosphorylation
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Quinoxalines
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Fibrosis
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Plasminogen Activators
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Cells, Cultured
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Blotting, Western
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Extracellular Matrix Proteins
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Transforming Growth Factor beta
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Collagen
Limits:
Humans
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Male
Language:
En
Journal:
Korean Journal of Urology
Year:
2012
Type:
Article