血管紧张素Ⅱ对帕金森病多巴胺能神经元线粒体的影响与机制

AngiotensinⅡ(AngⅡ) plays as a major peptide in central renin-angiotensin system ( RAS ) widely existing in mammal brain. It has been reported recently that AngⅡ involves in the neurodegeneration of dopaminergic (DA) neurons in Parkinson's disease (PD). However, the mechanism is still unclear. AngⅡ receptors are found highly expressed in DA neurons while the mitochondrial disorder of DA neurons is a major mechanism of PD. Therefore, we predict that AngⅡ may enhance the mitochondrial disorder and intensify the DA neurodegeneration in PD by binding to the membrane receptors of DA neurons. To validate the possible mechanism mentioned above, we would select rotenone-lesioned dopaminergic N27 cells as the cell model of PD. The changes of mitochondrial function would be observed when AngⅡ receptors, the expression of NADPH oxidase subtypes, autophapy, mitochondrial membrane potentials and mitochondrial KATP channels vary respectively in DA neurons. The probable signal cascade triggered by AngⅡ, which enhanced oxidase stresses in mitochondria, would be also explored in the experiments. Furthermore, the effects of central endogenous AngⅡ on the mitochondria of DA neurons would be verified in a rat rotenone-lesioned PD model. Carrying out all the experiments we were supposed will provide a new therapeutic strategy for PD.

脑内存在独立的肾素-血管紧张素系统（RAS），血管紧张素Ⅱ（AngⅡ）是脑内RAS最主要效应肽。近年发现AngⅡ参与帕金森病（PD）多巴胺能神经元的变性损伤，具体机制不清。由于多巴胺能神经元本身高表达AngⅡ受体，而多巴胺能神经元线粒体功能异常是导致PD发病的重要机制，我们推测"AngⅡ直接与多巴胺能神经元膜受体结合作用于线粒体促使神经元变性损伤"。为验证该推论，本课题选用鱼藤酮损伤多巴胺能N27细胞制作PD细胞模型，观察在AngⅡ作用下N27细胞膜受体、NADPH氧化酶亚型表达、自噬、线粒体膜电位、ATP敏感钾通道等的变化及其与线粒体损伤的关系；在此基础上探讨AngⅡ作用于线粒体强化氧化应激所依赖的信号级联；最后采用鱼藤酮损伤大鼠PD模型验证内源性AngⅡ对多巴胺能神经元线粒体的影响。本课题分别从细胞和动物两个层次探求AngⅡ参与PD多巴胺能神经元线粒体损伤的机制，为PD防治提供新思路。

血管紧张素Ⅱ（AngⅡ）是脑内肾素-血管紧张素系统（RAS）最主要效应肽,我们前期观察到脑内AngⅡ与阿尔兹海默病的神经变性有关，近年发现AngⅡ也参与帕金森病（PD）多巴胺能神经元的变性损伤，具体机制不清。本课题以AngⅡ对帕金森病多巴胺能神经元（CATH.a细胞）线粒体的影响为切入点，主要研究： 1、AngⅡ及其受体拮抗剂氯沙坦对CATH.a多巴胺能细胞凋亡及自噬的影响，及其可能的机制；2、AngⅡ及其受体拮抗剂氯沙坦对CATH.a多巴胺能细胞NADPH氧化酶及氧化应激的影响；3、AngⅡ及其受体拮抗剂氯沙坦对CATH.a多巴胺能细胞中线粒体通透转换孔（mPTP）的影响及其可能的机制。.结果表明：AngⅡ通过诱导自噬促进多巴胺能神经元凋亡；AngⅡ以依赖NADPH氧化酶活化的方式加剧了多巴胺能细胞的氧化应激；AngⅡ增强了mPTP的开放水平，继而进一步触发多巴胺能细胞凋亡，但以上作用均可被AT1受体氯沙坦所抑制。