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/jci18212
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发表时间：
2003-11
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影响因子：
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通讯作者：
R. Bataller;R. Schwabe;Youkyung H Choi;Liu Yang;Y. Paik;J. Lindquist;T. Qian;R. Schoonhoven;C. Hagedorn;J. Lemasters;D. Brenner
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文献类型：
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作者：
R. Bataller;R. Schwabe;Youkyung H Choi;Liu Yang;Y. Paik;J. Lindquist;T. Qian;R. Schoonhoven;C. Hagedorn;J. Lemasters;D. Brenner
血管紧张素II（AngII）是一种促氧化和纤维化的细胞因子。我们研究了NADPH氧化酶在血管紧张素II诱导的肝星状细胞（HSC），一种纤维化细胞类型的作用。人HSC表达非吞噬细胞NADPH氧化酶关键组分的mRNA。血管紧张素II磷酸化p47 phox，NADPH氧化酶的调节亚基，并诱导活性氧通过NADPH氧化酶活性的形成。Ang II磷酸化AKT和MAPK，并以氧化还原敏感的方式增加AP-1 DNA结合。血管紧张素II刺激DNA合成，细胞迁移，前胶原α 1（I）mRNA的表达，并分泌TGF-β 1和炎性细胞因子。这些作用被N-乙酰半胱氨酸和NADPH氧化酶抑制剂二亚苯基碘鎓减弱。此外，血管紧张素II诱导上调基因可能参与肝损伤愈合反应的氧化还原敏感的方式，通过微阵列分析评估。与WT细胞相比，从p47 phox-/-小鼠中分离的HSC对Ang II的反应迟钝。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，p47 phox-/-小鼠表现出减轻肝损伤和纤维化相比，野生型。此外，在p47 phox-/-小鼠中，平滑肌α-肌动蛋白的表达和TGF-β 1的表达减少。因此，NADPH氧化酶介导Ang II对HSC的作用，并在肝纤维化中起关键作用。
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 p47phox, 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-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox-/- 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, p47phox-/- mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle alpha-actin and expression of TGF-beta1 were reduced in p47phox-/- mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis.