AMINOPEPTIDASE A AND ANGIOTENSIN II METABOLISM

描述：（改编自摘要）这是一个应用程序， 研究外肽酶、氨肽酶-A（阿帕）和 其在调节局部肾素-血管紧张素系统中的潜在作用 在肾脏和大脑中。 这项研究的基础是假设， 阿帕是一种受调节的酶，其活性直接或间接地与 由血管紧张素修饰。 此外，建议 阿帕的活性在血管紧张素 当血管紧张素II（Ang II）水平升高或降低时， 很低 PKC和酪氨酸激酶依赖性磷酸化是 建议作为生化底物 负责修改 在阿帕活动中。 一个必然的假设是这样的想法 AIII而不是AII可能是CNS中的关键信号剂 阿帕在这一必要的转变中发挥着至关重要的作用。 为了解决这些假设，以下具体目标 将解决：1）确定血管紧张素II输注的影响， 血管紧张素转换酶抑制，钠饮食，阿帕抑制剂 AT 1受体拮抗剂对阿帕肾表达的影响。 2)确定 是否肾小球阿帕活性改变的动物， 实验性糖尿病或高血压。 3)确定影响 抑制阿帕活性对CNS中血管紧张素代谢的影响。 四、 确定磷酸化在调节阿帕活性中的作用。 第五章） 确定系膜细胞是否 阿帕活性可以是 调节 由 血管紧张素II受体介导的磷酸化机制。 6)确定血管紧张素II或其他细胞因子/血清 刺激阿帕基因在系膜或肾组织中表达的因子 上皮细胞 7)确定脑血管周细胞是否表达 血管紧张素Ⅱ受体和合同，在响应血管紧张素Ⅱ。

DESCRIPTION: (adapted from the abstract) This is an application to study the regulation of the ectopeptidase, aminopeptidase-A (APA) and its potential role in the modulation of local renin-angiotensin systems in the kidney and brain. The basis of the study is the hypothesis that APA is a regulated enzyme whose activity is directly or indirectly modified by angiotensins. Furthermore, it is suggested that the activity of APA is enhanced under conditions in which angiotensin levels are elevated and reduced when angiotensin II (Ang II) levels are low. PKC- and tyrosine kinase-dependent phosphorylations are proposed as biochemical substrates responsible for alterations in APA activity. A corollary hypothesis being addressed is the idea that AIII and not AII may be the critical signaling agent in the CNS and that APA plays a paramount role in this necessary conversion. In order to address these hypotheses, the following specific aims will be addressed: 1) Determine the effects of Ang II infusion, angiotensin converting enzyme inhibition, sodium diet, APA inhibitors and AT1 receptor antagonists on renal expression of APA. 2) Determine whether glomerular APA activity is altered in animals with experimental diabetes or hypertension. 3) Determine the effects of inhibition of APA activity on angiotensin metabolism in the CNS. 4) Determine the role of phosphorylation in regulating APA activity. 5) Determine whether mesangial cell APA activity can be regulated by an Ang II receptor-mediated phosphorylation mechanism. 6)Determine the mechanism by which Ang II or other cytokine/serum factors stimulate APA gene expression in mesangial or renal epithelial cells. 7) Determine if cerebrovascular pericytes express Ang II receptors and contract, in response to Ang II.