INTRACELLULAR RENIN-ANGIOTENSIN & BLOOD PRESSURE CONTROL

本提案的总体目标是确定 组织肾素抗降压素系统的功能和生理作用。 我们 将测试假设，在各种组织中的肾素功能， 分室化的方式，并将评估组织肾素的意义- 血管紧张素系统，特别是在血管系统中， 自发性高血压大鼠（SHR）血管张力升高， 其他原发性高血压动物模型。 初步结果表明，SHR的高血压持续后， 双侧肾切除术，但在 肾切除的SHR显著降低其血压。 这一发现 提示肾组织外肾素的重要性。 既然是 分泌的血管紧张素II（ANG II）在调节血管生成中起重要作用， 功能，而不是储存的肾素或血管紧张素II的量，我们有 开发了一种灵敏的方法来测量ANG II从 Krebs-Ringer灌注血管和肾脏。 新的合成和 肾素、血管紧张素受体和亲脂性的免疫抑制剂 将使用转化酶抑制剂（ACEI）。 纯大鼠肾素和 血管紧张素原将由重组DNA产生。 使用这些肾素-血管紧张素系统的抑制剂，我们将解决 组织中的肾素-血管紧张素是否在 自发性高血压 通过使用Krebs-Ringer灌注系统，我们 将确定ANG II生产的机制和控制， 血管系统、肾脏和其它含肾素的细胞。 的机制 将阐明哪种血管紧张素原可进入组织肾素。 具体而言，可能存在血管紧张素受体或转运系统 在含有肾素的细胞中将使用重组 血管紧张素原 组织肾素是否通过细胞外或 将研究细胞内机制。 细胞内途径 将研究肾素和ANG II的包装。 假设肾素 包装通过6-磷酸甘露糖基磷酸结合蛋白进行 和/或新发现的微粒体分选酶将使用富集的JG 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 迄今为止，这一点还不清楚，预计将对 我们对肾素依赖性的基本形式的机制的理解 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.