NEURAL-VASCULAR ANGIOTENSINS--ALTERATIONS IN SIGNAL TRANSDUCTION

该项目的重点是确定组织特异性 血管紧张素(Ang)多肽增加改变Ang多肽受体或 它们的信号转导机制。高血压病的遗传模型 将使用压力--转基因(TG)大鼠，其中包含小鼠 人-2基因。在这个模型中，血浆肾素没有升高，这表明 高血压是由于循环肾素的激活- 血管紧张素系统(RAS)然而，TG患者的血压升高 大鼠可通过血管紧张素转换酶(ACE)抑制剂或 AT1受体拮抗剂氯沙坦，暗示参与 高血压过程中的RAS。虽然循环中的血管紧张素转换酶水平 与对照组相比，TG组大鼠的多肽水平并未升高。 TG组大鼠脑内Ang I、Ang II和Ang-(1-7)含量较高。 此外，用血管紧张素转换酶抑制剂治疗甘油三酯大鼠或自发性高血压大鼠 Ang-(1-7)可降低脑内Ang受体的密度， 与脑室输注后血管紧张素受体的变化一致 血管紧张素。此外，我们之前的结果表明，Ang- (1-7)可以由组织特异性处理途径产生，并且 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 局部生产改变血管紧张素转运蛋白表达的血管紧张素转换酶 受体或它们对选择的信号通路的激活。这个 拟议的研究集中在两个组织RAS的细胞成分上-- 中枢RAS存在于参与控制 心血管功能与所含血管RAS的比较 血管壁，因为以前的研究表明血管紧张素转换酶 II受体及其信号转导机制在两种疾病中都发生了变化 自发性高血压大鼠的大脑和血管系统。确定血管紧张素转换酶是否 通过转基因、肾素mRNA、肾素的表达来提高水平 将测量活性、ANG多肽水平和ANG加工酶 在T-G大鼠的细胞中与其阴性胎鼠的细胞中。ANG多肽 细胞内特定信号通路的受体及其激活 将来自TG大鼠的细胞与其正常血压的细胞进行比较 文盲。最后，慢性升高的血管紧张素转换酶水平的影响 在大鼠体内可能存在内源性多肽AS，以及各种多肽酶 干扰血管紧张素转换酶系统的抑制剂或受体拮抗剂 将在体外研究多肽受体和信号通路， 分离的细胞。

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.