NEURAL-VASCULAR ANGIOTENSINS--ALTERATIONS IN SIGNAL TRANSDUCTION

神经血管血管紧张素——信号转导的改变

• 批准号: 6242316
• 负责人: Ann Ann Tallant
• 金额: $ 13.24万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242316
• 关键词: ACE inhibitors; RNase protection assay; angiotensin /renin /aldosterone hypertension; angiotensins; astrocytes; biological signal transduction; brain stem; disease /disorder model; enzyme activity; familial hypertension; gene expression; genetically modified animals; high performance liquid chromatography; hypothalamus; in situ hybridization; laboratory rat; neurobiology; neurons; nitric oxide; peptide hormone; phospholipase C; radioimmunoassay; renin angiotensin system

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.

该项目的重点是确定组织特异性 血管紧张素（ANG）肽的增加改变了ANG肽受体或 它们的信号转导机制。 高血的遗传模型 将使用压力 - 包含小鼠的转基因（TG）大鼠 Ren-2基因。 在此模型中，血浆肾素没有升高，表明 高血压是由于循环肾素的激活 血管紧张素系统（RAS）。 但是，TG的血压升高 可以通过血管紧张素转化酶（ACE）抑制剂或 AT1受体拮抗剂Losartan，暗示 在高血压过程中的RA。 虽然循环水平 与对照组大鼠相比，TG大鼠的肽没有升高 TG大鼠的大脑包含更高水平的ANG I，ANG II和ANG-（1-7）。 此外，用ACE抑制剂对TG大鼠或SHR的治疗升高 Ang-（1-7）水平，并降低大脑中的人体受体的密度， 与ICV输注后ANG受体的改变一致 Ang肽。 此外，我们以前的结果表明 （1-7）可以通过组织特定的处理途径产生 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升高 ANG肽的局部产生，改变了ANG肽的表达 受体或他们的精选信号通路的激活。 这 提出的研究集中于两个组织Ras的细胞成分 - 参与控制的大脑区域中的中央拉斯 与包含的血管RA相比，心血管功能 血管的壁，因为先前的研究表明Ang II受体及其信号转导机制在两者中都发生了改变 SHR的大脑和脉管系统。 确定ANG肽是否 通过转基因，肾素mRNA，肾素的表达升高水平 将测量活动，ANG肽水平和ANG加工酶 在T g大鼠的细胞中，与其负同窝仔。 ANG肽 受体及其在细胞中特定信号通路的激活 从TG大鼠将其正常型细胞进行比较 核心。 最后，慢性升高水平的ANG的影响 大鼠和各种肽酶内源性发生的肽可能发生 干扰RA的抑制剂或受体拮抗剂，在ANG上 肽受体和信号通路将在体外研究， 孤立的细胞。