Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl(4)-induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction.
Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl(4)-induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction.
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Smad3基因C末端磷酸化位点突变通过促进pSmad2L/C介导的信号转导加剧CCl(4)诱导的肝纤维化。
DOI：
10.1007/s00210-021-02114-1
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yang Yan
中科院分区：
文献类型：
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作者：
Yang Juan;Gong Yongfang;Xu Wenjing;Li Lili;Shi Zhenghao;Wang Qin;He Yinghao;Zhang Chong;Luo Chenchen;Fang Zhirui;Yang Yan
目前研究证实，Smads作为TGF-β信号通路的介导因子，在肝脏疾病的发生发展过程中受到结构域特异性位点磷酸化的严格控制。通常，Smad 3磷酸化异构体pSmad 3L和pSmad 3C具有可逆性和拮抗性，pSmad 2L/C可与pSmad 3L共同作用，通过刺激派-1表达和ECM合成传递致纤维化信号。我们最近的研究发现，pSmad 3C突变可能在肝损伤的早期阶段发挥积极作用，并减弱了丹参素B的抗肝纤维化-癌的作用。然而，pSmad 3C突变是否加速pSmad 2L/C介导的信号转导在肝纤维化过程中仍然是模糊的。目前，构建Smad 3基因C端磷酸化位点突变杂合子（pSmad 3C +/-）小鼠，以探讨pSmad 3C是否以及如何通过抑制pSmad 2L/C介导的信号转导来延缓CCl 4诱导的肝纤维化。12只6周龄pSmad 3C +/-C57 BL/6 J小鼠腹腔注射CCl 4 6周诱导肝纤维化。结果表明，pSmad 3C基因突变可导致HT-CCl 4小鼠肝脏相对重量、生化指标、胶原纤维和纤维化间隔的增加，参与肝纤维化的发生。此外，在CCl 4诱导的pSmad 3C +/-小鼠中，纤维化相关蛋白TGF-β1、pSmad 2C、pSmad 2L和派-1也增加。提示pSmad 3C突变可加重肝纤维化的发生，其机制可能与pSmad 2L/C介导的信号转导有关。
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 CCl4-induced hepatic fibrogenesis by inhibiting pSmad2L/C-mediated signaling transduction. Twelve 6-week-old pSmad3C+/-C57BL/6J mice were intraperitoneally injection with CCl4for 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-CCl4mice. Furthermore, fibrotic-related proteins TGF-β1, pSmad2C, pSmad2L, and PAI-1 were also increased in CCl4-induced pSmad3C+/-mice. These results suggest that pSmad3C mutation exacerbates hepatic fibrogenesis which relates to intensifying pSmad2L/C-mediated signaling transduction.