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、氨基肽酶-A(APA)和 它在局部肾素-血管紧张素系统调节中的潜在作用 在肾脏和大脑中。这项研究的基础是这样一个假设 APA是一种受调节的酶，其活性直接或间接地 被血管紧张素修饰。此外，有人建议， 在血管紧张素转换为血管紧张素的条件下，APA的活性增强 当血管紧张素II(Ang II)水平升高或降低时 都很低。依赖于PKC和酪氨酸激酶的磷酸化是 被认为是造成变化的生化底物 在APA活动中。正在讨论的一个必然假设是这样的想法 AIII而非AII可能是中枢神经系统中的关键信号转导因子 而APA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，以下是具体目标 将解决：1)确定血管紧张素转换酶II的效果， 血管紧张素转换酶抑制、钠饮食、APA抑制剂 AT1受体拮抗剂对肾组织APA表达的影响。2)确定 肾小球APA活性是否发生改变 实验性糖尿病或高血压。3)确定 APA活性对中枢血管紧张素代谢的抑制。4) 确定磷酸化在调节APA活性中的作用。5) 确定系膜细胞APA活性是否可以调节 通过Ang II受体介导的磷酸化机制。 6)确定Ang II或其他细胞因子/血清的作用机制 促肾小球系膜或肾脏APA基因表达的因素 上皮细胞。7)确定脑血管周细胞是否表达 Ang II受体和收缩，作为对Ang II的反应。

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.