INTRACELLULAR RENIN-ANGIOTENSIN & BLOOD PRESSURE CONTROL

这项提案的总体目标是定义 组织肾素抗紧张素系统的功能和生理作用。我们 将检验这样一种假设，即各种组织中的肾素在 并将评价组织肾素的意义。 血管紧张素系统，特别是在血管系统中，在 自发性高血压大鼠(SHR)血管张力升高 其他高血压病动物模型。 初步结果显示，自发性高血压患者持续存在高血压。 双侧肾切除，但输注肾素抑制剂 肾切除自发性高血压大鼠可显著降低血压。这一发现 提示额外肾组织肾素的重要性。因为它是 分泌型血管紧张素II(Ang II)在血管调节中的重要作用 而不是储存的肾素或血管紧张素II的量，我们有 建立了一种灵敏的方法来测量血管紧张素II的释放率 Krebs-Ringer灌流血管和肾脏。新的合成纤维和 肾素、血管紧张素受体和亲脂性免疫抑制剂 将使用转化酶抑制剂(ACEI)。纯大鼠肾素和 血管紧张素原将从重组DNA中产生。 使用这些肾素-血管紧张素系统的抑制剂，我们将解决 关于组织肾素-血管紧张素是否在 自发性高血压。通过使用Krebs-Ringer灌流系统，我们 将决定Ang II的生产机制和控制 血管、肾脏和其他含有肾素的细胞。这个机制是通过 哪些血管紧张素原获得组织肾素的途径将被阐明。 具体来说，可能存在血管紧张素受体或运输系统 在含有肾素的细胞中将使用重组 血管紧张素原。组织肾素是通过细胞外途径发挥作用还是通过细胞外途径发挥作用 细胞内的机制将被研究。细胞内途径 肾素和血管紧张素II的包装将进行研究。肾素的假说 包装以6-磷酸甘露醇结合蛋白的方式进行 和/或新发现的微粒体分类酶将使用浓缩的JG进行测试 和其他类型的细胞。 这些研究将阐明组织肾素的作用和作用机制 到目前为止还不清楚，预计将对 我们对肾素依赖形式本质的机制的认识 高血压。

The overall objective of this proposal is to define the mechanism of function and physiological role of tissue renin antiotensin systems. We will test the hypothesis that renin in various tissues functions in a compartmentalized way, and will evaluate the significance of tissue renin- angiotensin systems, particularly that in the vascular system, in the elevation of vascular tone in spontaneously hypertensive rats (SHR) and other animal models of essential hypertension. Preliminary results indicate that hypertension in SHR persists after bilateral nephrectomy, but infusion of a renin inhibitor in the nephrectomized SHR markedly lowers its blood pressure. This finding suggests he importance of extra renal tissue renin. Since it is the secreted angiotensin II (ANG II) which is important in regulating vascular functions rather than the amount of the stored renin or ANG II, we have developed a sensitive method to measure the rate of ANG II release from the Krebs-Ringer perfused vasculatures and kidney. New synthetic and immunological inhibitors of renin, angiotensin receptor and lipophilic converting enzyme inhibitors (ACEI) will be used. Pure rat renin and angiotensinogen will be produced from recombinant DNAs. Using these inhibitors of the renin-angiotensin system, we will address the questions as to whether tissue renin-angiotensin plays the major role in spontaneous hypertension. By using the Krebs-Ringer perfusion system, we will determine the mechanism and control of ANG II production from vasculature, kidney and other renin containing cells. The mechanism by which angiotensinogen gain access to tissue renin will be clarified. Specifically, possible presence of angiotensin receptor or transport system in renin containing cells will be looked for using recombinant angiotensinogen. Whether tissue renin works by an extracellular or intracellular mechanism will be investigated. Intracellular pathway of packaging of renin and ANG II will be studied. The hypothesis that renin packaging takes place by way of 6-phosphymannosyl phosphate binding protein and/or newly discovered microsomal sortase will be tested using enriched JG and other types of cells. These studies will clarify the role and mechanism of action of tissue renin which has been unclear to date and expected to contribute importantly to our understanding of the mechanism of renin dependent forms of essential hypertension.