Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat
Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat
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DOI：
10.1016/j.regpep.2006.07.011
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发表时间：
2007-01-10
影响因子：
--
通讯作者：
Yang, Xishan
中科院分区：
文献类型：
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作者：
Li, Xu;Meng, Ying;Yang, Xishan
背景/目的：肝内肾素-血管紧张素-醛固酮系统(RAAS)在肝纤维化形成中起关键作用。然而，血管紧张素II(Ang II)和醛固酮(Aldo)对核因子-kappaB(NF-kappa B)和活性蛋白-1(AP-1)途径在肝纤维化中的作用机制尚不清楚。本研究旨在探讨Ang II和Aldo在肝纤维化过程中影响核因子-kappaB和AP-1通路的信号转导机制。方法：采用大鼠肝纤维化模型，观察AECI和血管紧张素III型受体(AT-1受体)拮抗剂对肝组织核因子-kappaB活性的影响。在体外，肝星状细胞(HSCs)-T6细胞预先孵育1h或与细胞外信号调节激酶(ERK)的特异性抑制剂U0126、厄贝沙坦和N-乙酰半胱氨酸共同孵育1h，然后再加入Ang II或Aldo。用凝胶迁移率改变分析法(EMSA)检测核因子-kappaB和AP-1的DNA结合活性。Western印迹法检测I-kappa Bα和磷酸化p42/44的表达。逆转录-聚合酶链式反应检测肿瘤坏死因子α和α1(I)前胶原基因的表达。结果：AECI和AT-1受体阻滞剂通过抑制肝组织中核因子-kappaB的活化而发挥抗纤维化作用。Ang II和Aldo通过氧化还原敏感的方式抑制I kappa Bα的表达，从而增加HSC的核因子-kappa B活性和核因子-kappaB靶基因-TNFα的表达。Ang II和Aldo还通过ERK 1/2途径显著增加HSCAP-1活性和AP-1靶基因α1(I)前胶原mRNA的表达，且具有氧化还原敏感性。结论：激活核因子-kappaB和AP-1通路参与了RAAS诱导的肝纤维化过程。(C)2006爱思唯尔B.V.保留所有权利。
Background/aims: Intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis of liver. However, the signal transduction mechanism underlying effects of Angiotensin II (Ang II) and Aldosterone (Aldo) on Nuclear Factor-kappa B (NF-kappa B) and active protein-1 (AP-1) pathway in hepatic fibrogenesis remains to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying effects of Ang II and Aldo on NF-kappa B and AP-1 pathway during hepatic fibrogenesis. Methods: To assess the effect of AECI and Angiotensin II type I receptor (AT-1 receptor) blocker on NF-kappa B activity in liver, a model of fibrosis was performed in rat. In vitro, hepatic stellate cells (HSCs)-T6 cells were preincubated for 1 h or riot with U0126, a specific inhibitor of extracellular signal regulated kinase (ERK), irbesartan, and N-acetylcysteine prior to exposure to Ang II or Aldo for the indicated times. DNA binding activity of NF-kappa B and AP-1 were analyzed by Electrophoretic mobility shift assay (EMSA). Western blot was used to detect expression of I kappa B alpha and Phospho-P42/44. RT-PCR was used to detect the expressions of tumor necrosis factor alpha (TNF alpha) mRNA and alpha 1 (I) procollagen mRNA. Results: AECI and AT-1 receptor blocker exert anti-fibrosis effect through inhibiting NF-kappa B activation in liver. Ang II and Aldo increase HSCs NF-kappa B activity and NF-kappa B target gene-TNF alpha expression by inhibiting I kappa B alpha expression in a redox-sensitive manner. Ang II and Aldo also markedly increase HSCs AP-1 activity and AP-1 target gene-alpha 1 (I) procollagen mRNA expression via ERK 1/2 pathway in a redox-sensitive manner. Conclusions: These results show that stimulation of NF-kappa B and AP-1 pathway mediate hepatic fibrogenesis induced by intrahepatic RAAS. (c) 2006 Elsevier B.V. All rights reserved.