Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl 4 -induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2021-08, Vol.394 (8), p.1779
• Main Authors: Yang, Juan, Gong, Yongfang, Xu, Wenjing, Li, Lili, Shi, Zhenghao, Wang, Qin, He, Yinghao, Zhang, Chong, Luo, Chenchen, Fang, Zhirui, Yang, Yan
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride; Disease Models, Animal; Liver Cirrhosis - genetics; Liver Cirrhosis - physiopathology; Mice; Mice, Inbred C57BL; Mutation; Phosphorylation - genetics; Serpin E2 - metabolism; Signal Transduction - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 1432-1912

Current researches have confirmed that Smads, mediators of TGF-β signaling, are strictly controlled by domain-specific site phosphorylation in the process of hepatic disease. Usually, Smad3 phospho-isoform pSmad3L and pSmad3C are reversible and antagonistic; pSmad2L/C could act together with pSmad3L by stimulating PAI-1 expression and ECM synthesis to transmit fibrogenic signals. Our recent study found that pSmad3C mutation is supposed to perform a vigorous role on the early phase of liver injury and abates salvianolic acid B's anti-hepatic fibrotic-carcinogenesis. However, whether pSmad3C mutation expedites pSmad2L/C-mediated signaling transduction during hepatic fibrogenesis remains vague. Presently, Smad3 gene C-terminal phosphorylation site mutation heterozygote (pSmad3C ) mice were constructed to probe if and how pSmad3C retards CCl -induced hepatic fibrogenesis by inhibiting pSmad2L/C-mediated signaling transduction. Twelve 6-week-old pSmad3C C57BL/6J mice were intraperitoneally injection with CCl for 6 weeks to induce liver fibrogenesis. Results showed that pSmad3C mutation aggravates the relative liver weight, biochemical parameters, collagenous fibers and fibrotic septa formation, contributes to fibrogenesis in HT-CCl mice. Furthermore, fibrotic-related proteins TGF-β , pSmad2C, pSmad2L, and PAI-1 were also increased in CCl -induced pSmad3C mice. These results suggest that pSmad3C mutation exacerbates hepatic fibrogenesis which relates to intensifying pSmad2L/C-mediated signaling transduction.