PRESSURE NATRIURESIS MEDIATED BY EXTRACELLULAR cGMP

描述（由申请方提供）：压力-尿钠排泄是哺乳动物生理学中的主要调节机制，其中血压（BP）急性升高诱导肾钠排泄快速增加。了解介导压力尿钠排泄的机制是至关重要的，因为实验动物和人类中所有形式的高血压都伴随着对血压升高的不良尿钠排泄反应。压力性尿钠排泄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（RI）鸟苷环3 '，5'-单磷酸（cGMP）（与细胞内cGMP相反）和肾近端小管（RPT）细胞蛋白激酶G（PKG）在介导压力-尿钠排泄中的作用，为了确定一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-细胞外R1 cGMP-细胞PKG途径介导对肾灌注压（RPP）急性升高的利钠反应，以确定所涉及的特异性PKG亚型，并鉴定在大鼠中盐敏感性高血压和自发性高血压中缺乏的沿着该途径的点。中心假设是细胞外Rl cGMP在经由PKG的压力尿钠排泄中起主要关键作用，并且该途径中的缺陷导致盐敏感性和高血压。具体的目的是（1）检验以下假设：压力-尿钠排泄由RPT细胞中的细胞外Rl cGMP和细胞PKG（I型）介导，和（2）检验以下假设：盐敏感性高血压中的压力-尿钠排泄的抑制是由于细胞外Rl cGMP产生的缺陷，而自发性高血压中的压力-尿钠排泄的抑制是由于Rl cGMP作用的缺陷。具体目的的证明将鉴定和表征细胞外Rl 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标。

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.