NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis
NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis
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DOI：
10.1172/jci200318212
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Brenner, DA
中科院分区：
文献类型：
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作者：
Bataller, R;Schwabe, RF;Brenner, DA
血管紧张素II（Ang II）是一种促氧化剂和促纤维化细胞因子。我们研究了NADPH氧化酶在血管紧张素II对肝星状细胞（HSCs）（一种促纤维化细胞类型）诱导作用中的角色。人肝星状细胞表达非吞噬性NADPH氧化酶关键组分的信使核糖核酸（mRNAs）。血管紧张素II使NADPH氧化酶的调节亚基p47phox磷酸化，并通过NADPH氧化酶活性诱导活性氧物质形成。血管紧张素II使蛋白激酶B（AKT）和丝裂原活化蛋白激酶（MAPKs）磷酸化，并以氧化还原敏感的方式增加激活蛋白1（AP - 1）与DNA的结合。血管紧张素II刺激DNA合成、细胞迁移、I型前胶原α1信使核糖核酸表达以及转化生长因子β1（TGF - β1）和炎性细胞因子的分泌。这些作用被N - 乙酰半胱氨酸和二亚苯基碘鎓（一种NADPH氧化酶抑制剂）减弱。此外，通过微阵列分析评估，血管紧张素II以氧化还原敏感的方式诱导可能参与肝脏创伤愈合反应的基因上调。从p47phox - / - 小鼠分离的肝星状细胞与野生型（WT）细胞相比，对血管紧张素II的反应减弱。我们还评估了NADPH氧化酶在实验性肝纤维化中的作用。胆管结扎后，与野生型对应小鼠相比，p47phox - / - 小鼠显示出肝脏损伤和纤维化减轻。此外，p47phox - / - 小鼠中平滑肌α - 肌动蛋白的表达以及转化生长因子β1的表达降低。因此，NADPH氧化酶介导血管紧张素II对肝星状细胞的作用，并在肝纤维化形成中起关键作用。
Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II-induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47(phox), a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II stimulated DNA synthesis, cell migration, procollagen alpha1(I) mRNA expression, and secretion of TGF-beta1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, Ang II induced upregulation of genes potentially involved in hepatic wound-heating response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47(phox-/-) mice displayed a blunted response to Ang II compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47(phox-/-) mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle a-actin and expression of TGF-beta1 were reduced in p47(phox-/-) mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis.