Angiotensin II and NADPH Oxidase in Hepatic Fibrosis

描述（由申请人提供）：肝纤维化，细胞外基质（ECM）蛋白的积累，发生在大多数类型的慢性肝病中。肝纤维化进展为肝硬化，随后伴有门静脉高压症、肝衰竭和肝细胞癌。活化的肝星状细胞（HSC）是纤维化肝脏中主要的ECM产生细胞，并且已经鉴定出关键的纤维化信号，包括转化药物因子β（TGF β）、活性氧（ROS）和Ang II。我们已经证明，在活化的HSC中由Ang II激活的关键信号通路是通过NADPH氧化酶内源性产生ROS，并且下游影响模块HSC增殖、ECM蛋白的产生和炎性细胞因子的合成。因此，我们已经开始阐明炎症，血管紧张素II，活性氧和肝纤维化之间的机制关系。我们希望追求四个具体的目标，以进一步表征血管紧张素II在肝纤维化和下游激活NADPH氧化酶的作用。 作为这一建议基础的基本假设如下： 1.肾素-血管紧张素原系统是肝纤维化的重要途径。 2.血管紧张素II的影响，包括基因表达的变化的主要介质是NADPH氧化酶的激活。 3.其他纤维化因子也诱导NADPH氧化酶，使得该酶成为活性氧物质的产生和随后的纤维化诱导的关键介质。 4.对血管紧张素II和NADPH氧化酶介导肝纤维化的机制的新认识将有助于开发治疗肝纤维化疾病的新疗法。 该提案的具体目标是： 1.目的：明确肝星状细胞NADPH氧化酶复合物的组成。 2.探讨抑制血管紧张素Ⅱ对肝纤维化及肝星状细胞凋亡的影响。3.探讨血管紧张素原基因在肝纤维化模型中的作用。 4.确定除Ang II外的其他肝纤维化介质是否激活NADPH氧化酶。

DESCRIPTION (provided by applicant): Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins, occurs in most types of chronic liver diseases. Liver fibrosis progresses to cirrhosis with subsequent portal hypertension, hepatic failure, and hepatocellular carcinoma, Activated hepatic stellate cells (HSCs) are the major ECM producing cell in the fibrogenic liver and key fibrogenic signals have been identified, including transforming drug factor beta (TGFbeta), reactive oxygen species (ROS), and Ang II. We have demonstrated that the key signaling pathway activated by Ang II in activated HSC is the endogenous generation of ROS by NADPH oxidase and that the downstream effects module HSC proliferation, production of ECM proteins, and synthesis of inflammatory cytokines. Thus we have begun to elucidate the mechanistic relationship between inflammation, Ang II, reactive oxygen species, and hepatic fibrosis. We wish to pursue four specific aims to further characterize the role of Ang II in hepatic fibrosis and the downstream activation of NADPH oxidase. The underlying hypotheses that serve as the basis for this proposal are the following: 1.The renin-angiotensinogen system is a critical pathway in hepatic fibrosis. 2. The major mediator of the effects of Ang II including changes in gene expression is the activation of NADPH oxidase. 3. Other fibrogenic factors also induce NADPH oxidase, so that this enzyme becomes the critical mediator of the generation of reactive oxygen species and subsequent induction of fibrogenesis. 4. New insights into the mechanisms by which Ang II and NADPH oxidase mediate hepatic fibrogenesis will lead to the development of novel therapies for patients with fibrotic liver diseases. The specific aims of the proposal are: 1. To define the components of the NADPH oxidase complex in hepatic stellic cells. 2. To assess the effect of inhibiting Ang II on hepatic fibrosis and hepatic stellate cell apoptosis. 3. To assess the effect of titrating the angiotensinogen gene in models of hepatic fibrosis. 4. To determine if other mediators of hepatic fibrosis in addition to Ang II activate NADPH oxidase.