PRESSURE NATRIURESIS MEDIATED BY EXTRACELLULAR cGMP

描述（由申请人提供）：压力尿钠排泄是哺乳动物生理学中的主要调节机制，血压（BP）急剧升高会导致肾钠排泄快速增加。了解介导压力尿钠排泄的机制至关重要，因为实验动物和人类的所有形式的高血压都伴随着对血压升高的利尿钠反应缺陷。压力尿钠的潜在机制尚不清楚。该项目的总体目标是了解细胞外肾间质 (Rl) 鸟苷环 3', 5'-单磷酸 (cGMP) 相对于细胞内 cGMP 和肾近曲小管 (RPT) 细胞蛋白激酶 G (PKG) 在介导压力尿钠排泄中的作用，以确定一氧化氮 (NO)-可溶性鸟苷酸环化酶 (sGC)-细胞外 Rl cGMP-细胞是否PKG 途径介导对肾灌注压 (RPP) 急剧增加的利尿钠反应，以确定所涉及的特定 PKG 亚型，并确定该途径中在大鼠盐敏感性高血压和自发性高血压中缺乏的点。核心假设是，细胞外 R1 cGMP 在通过 PKG 的压力尿钠排泄中发挥着重要的关键作用，并且该途径的缺陷导致盐敏感性和高血压。具体目的是（1）检验压力尿钠排泄是由RPT细胞中的细胞外Rl cGMP和细胞PKG（I型）介导的假设，以及（2）检验盐敏感性高血压中压力尿钠排泄的抑制是由于细胞外Rl cGMP产生的缺陷和自发性高血压是由于Rl cGMP作用缺陷引起的假设。具体目标的证明将鉴定和表征细胞外R1 cGMP的新作用，并为高血压和与钠潴留相关的其他疾病状态提供潜在的治疗靶点。

DESCRIPTION (provided by applicant): Pressure-natriuresis is the major regulatory mechanism in mammalian physiology whereby an acute elevation in blood pressure (BP) induces a rapid increase in renal sodium excretion. An understanding of the mechanisms that mediate pressure-natriuresis is critical, because all forms of hypertension in experimental animals and man are accompanied by a defective natriuretic response to increased BP. The underlying mechanism of pressure-natriuresis is unknown. The overall goals of this project are to understand the role of extracellular renal interstitial (Rl) guanosine cyclic 3', 5'-monophosphate (cGMP), as opposed to intracellular cGMP, and renal proximal tubule (RPT) cell protein kinase G (PKG) in mediating pressure-natriuresis, to determine whether the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-extracellular Rl cGMP-cellular PKG pathway mediates the natriuretic response to an acute increase in renal perfusion pressure (RPP), to determine the specific PKG isoform involved and to identify the point(s) along this pathway which is (are) deficient in salt-sensitive hypertension and spontaneous hypertension in the rat. The central hypothesis is that extracellular Rl cGMP plays a major critical role in pressure natriuresis via PKG and that defects in this pathway lead to salt-sensitivity and hypertension. The specific aims are (1) to test the hypothesis that pressure-natriuresis is mediated by extracellular Rl cGMP and cellular PKG (type I) in RPT cells and (2) to test the hypothesis that the dampening of pressure-natriuresis in salt-sensitive hypertension is due to a defect in extracellular Rl cGMP production and in spontaneous hypertension is due to a defect in Rl cGMP action. Proof of the specific aims will identify and characterize a novel role of extracellular Rl cGMP and provide a potential therapeutic target for hypertension and other disease states associated with sodium retention.