NEURAL-VASCULAR ANGIOTENSINS--ALTERATIONS IN SIGNAL TRANSDUCTION

本项目的重点是确定是否组织特异性 血管紧张素（Ang）肽的增加改变Ang肽受体，或 它们的信号转导机制。 高血压的遗传模型 将使用压力-转基因（TG）大鼠，其中含有小鼠 Ren-2基因。 在该模型中，血浆肾素未升高，表明 高血压是由于激活循环肾素- 血管紧张素系统（RAS）。 然而，TG中的血压升高 大鼠可通过血管紧张素转换酶（ACE）抑制剂或 AT 1受体拮抗剂氯沙坦，涉及参与 高血压过程中的RAS 虽然循环中的血管紧张素 与对照组大鼠相比，TG大鼠中的肽水平没有升高， TG组大鼠脑组织中Ang I、Ang II和Ang-（1-7）水平均高于对照组。 此外，用ACE抑制剂治疗TG大鼠或SHR， Ang-（1-7）水平并降低脑中Ang受体的密度， 与ICV输注后Ang受体的改变一致 血管紧张素肽。 此外，我们以前的研究结果表明，Ang- (1-7)可以通过组织特异性处理途径产生， Ang-（1-7）激活不同的信号通路。 我们的假设是 Ren-2转基因的组织特异性表达导致了 局部产生改变Ang肽表达的Ang肽 受体或其激活选择信号通路。 的 提出的研究集中在两种组织RAS的细胞成分上-- 中枢RAS存在于参与控制 心血管功能与血管RAS相比， 血管壁，因为以前的研究表明，血管紧张素 II受体和它们的信号转导机制在两种细胞中都发生了改变， SHR的大脑和脉管系统。 为了确定血管紧张素肽 水平通过转基因、肾素mRNA、肾素-β-D-半乳糖苷酶和肾素-β-D-半乳糖苷酶的表达而升高。 将测量血管紧张素活性、血管紧张素肽水平和血管紧张素加工酶 与阴性同窝出生的大鼠相比。 Ang肽 受体及其在细胞中的特定信号传导途径的激活 将来自TG大鼠的细胞与来自其血压正常的大鼠的细胞进行比较。 小伙伴们 最后，慢性升高的Ang水平 肽，如可能在大鼠中内源性发生的，以及各种肽酶 干扰RAS的抑制剂或受体拮抗剂， 肽受体和信号通路将在体外研究， 孤立的细胞

The focus of this project is to determine whether tissue-specific increases in angiotensin (Ang) peptides alter Ang peptide receptors or their mechanisms of signal transduction. A genetic model of high blood pressure will be used--the transgenic (TG) rat which contains the mouse Ren-2 gene. In this model, plasma renin is not elevated, suggesting that the hypertension is to due to activation of the circulating renin- angiotensin system (RAS). However, the elevated blood pressures in TG rats can be reduced by angiotensin converting enzyme (ACE) inhibitors or the AT1 receptor antagonist losartan, implicating the participation of the RAS in the hypertensive process. Although circulating levels of Ang peptides were not elevated in TG rats compared to controls rats, the brains of TG rats contained higher levels of Ang I, Ang II and Ang-(1-7). Furthermore, treatment of TG rats or SHRs with ACE inhibitors elevates Ang-(1-7) levels and decreases the density of Ang receptors in the brain, in agreement with alterations in Ang receptors following ICV infusions of Ang peptides. In addition, our previous results have shown that Ang- (1-7) can be generated by tissue specific processing pathways and that Ang-(1-7) activates distinct signalling pathways. Our hypothesis is that the tissue-specific expression of the Ren-2 transgene results in elevated local production of Ang peptides which alter expression of Ang peptide receptors or their activation of select signalling pathways. The proposed studies focused on the cellular components of two tissue RAS-- the central RAS present in brain areas which participate in control of cardiovascular function as compared to the vascular RAS contained within the wall of the blood vessel, since previous studies have shown that Ang II receptors and their signal transduction mechanisms are altered in both the brain and vasculature of the SHR. To determine whether Ang peptide levels are elevated by the expression of the transgene, renin mRNA, renin activity, Ang peptide levels and Ang processing enzymes will be measured in cells from T G rats versus their negative littermates. Ang peptides receptors and their activation of specific signalling pathways in cells from TG rats will be compared to cells from their normotensive littemates. Finally, the effects of chronic elevated levels of Ang peptides as may occur endogenously in the rat, and of various peptidase inhibitors or receptor antagonists which interfere with the RAS, on Ang peptide receptors and signalling pathways will be studied in vitro, in isolated cells.