Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression
Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression
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Gremlin1 通过上调 TGF-β 表达加速肝星状细胞激活
DOI：
10.1089/dna.2017.3707
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发表时间：
2017
影响因子：
3.1
通讯作者：
Wu Jiang-Feng
中科院分区：
文献类型：
--
作者：
Zhang Yan-Qiong;Wan Lin-Yan;He Xiao-Min;Ni Yi-Ran;Wang Chang;Liu Chang-Bai;Wu Jiang-Feng
Gremlin1是骨形态发生蛋白-7的拮抗剂，也是转化生长因子-β信号通路的靶基因之一，在胚胎发育过程中起重要作用，其表达随年龄增长而减弱。为探讨gremlin1在肝纤维化中的表达及其与肝星状细胞(HSC)活化的因果关系，采用实时定量聚合酶链式反应(RT-qPCR)和免疫组织化学方法检测了猪血清诱导的小鼠肝纤维化模型中gremlin1的表达。观察肝纤维化小鼠肝脏的外部特征、组织学、肝功能、胶原沉积及肝纤维化相关基因(COLIVα2和COLIVα2)的表达。在培养的HSC-T6细胞中，用免疫印迹法检测α-SMA、COL-1和α-α的表达。结果表明，肝纤维化小鼠肝组织中Gremlin1基因的表达明显增强，与Coliα2和ColIVα2的表达增强一致。Gremlin1的表达增加与胶原沉积的面积相同。此外，α-SMA、ColiGRNA1和α-β1的表达与gremlin1的表达是一致的，不仅在高表达gremlin1的HSC-T6中，而且在用特异性siRNA下调gremlin1的HSC-T6中也是如此。研究结果表明，gremlin1可能在肝纤维化的发展过程中发挥重要作用，并调节HSC的激活。
Gremlin1, the antagonist of bone morphogenetic protein-7 and one of the target genes of transforming growth factor (TGF)-β signal pathway, plays an important role in embryonic development and its expression decreases along with aging. To explore the expression of gremlin1 in liver fibrosis and the causal link between gremlin1 and hepatic stellate cell (HSC) activation, we detected the expression of gremlin1 in mice with hepatic fibrosis induced by porcine serum using real time quantitative PCR (RT-qPCR) and immunohistochemical staining. The hepatic fibrosis mice were evaluated by the external feature of the liver, histology, hepatic function, collagen deposition, and the expression of fibrosis-related genes (genes COLIα2 and COLIVα2) in the liver. In the HSC-T6, western blotting was used to analyze the expression of α-smooth muscle actin (α-SMA), COL1α, and TGF-β1 in conditions of overexpression of gremlin1 or gremlin1 being knocked down by specific siRNA, respectively. The results showed that the mRNA expression of the gremlin1 gene was significantly increased consistent with increased expression of COLIα2 and COLIVα2 in the liver tissue of the hepatic fibrosis mice. Increased expression of gremlin1 coincided with the same area of the collagen deposition. Furthermore, the results also showed that the expression of α-SMA, COLIα1, and TGF-β1 was consistent with the expression of gremlin1 not only in the HSC-T6 overexpressing gremlin1 but also in the HSC-T6 that gremlin1 is knocked down by specific siRNA. The findings suggest that gremlin1 might play an important role in the progression of hepatic fibrosis and that it modulates HSC activation.