PRESSURE NATRIURESIS MEDIATED BY EXTRACELLULAR cGMP

细胞外 cGMP 介导的压力尿钠

• 批准号: 7666217
• 负责人: ROBERT MUNSON CAREY
• 金额: $ 44.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666217
• 关键词: Acute; Animals; Anions; Arginine; Blood Pressure; Cells; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Defect; Disease; Endocrine; Excretory function; Extracellular Fluid; Goals; Guanosine; Guanosine Triphosphate; Hypertension; Kidney; Lead; Left; Mediating; Mediator of activation protein; Methods; Natriuresis; Nitric Oxide; Organism; Pathway interactions; Perfusion; Physiology; Play; Principal Investigator; Protein Isoforms; Proximal Kidney Tubules; Rattus; Role; Signal Transduction; Signaling Molecule; Sodium; Soluble Guanylate Cyclase; System; Testing; cGMP production; extracellular; in vivo; interstitial; kidney vascular structure; man; novel; paracrine; pressure; response; salt sensitive; saluretic; therapeutic target

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.

描述(申请人提供)：血压-钠尿是哺乳动物生理学中的主要调节机制，血压的急剧升高会导致肾脏钠排泄的迅速增加。了解调节血压-钠尿的机制至关重要，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有缺陷的钠尿反应。压力性钠尿的潜在机制尚不清楚。这个项目的总体目标是了解细胞外肾间质(RL)环3‘，5’-单磷酸(CGMP)而不是细胞内cGMP和肾近端小管(RPT)细胞蛋白激酶G(PKG)在调节压力-钠尿中的作用，以确定一氧化氮(NO)-可溶性鸟苷酸环酶(SGC)-细胞外RL cGMP-细胞PKG通路是否介导了对肾脏灌流压(RPP)急剧增加的利钠反应。确定参与该通路的特异性蛋白激酶G亚型，并确定该通路在盐敏感性高血压和自发性高血压大鼠中缺失的点(S)。中心假说是细胞外RL cGMP通过PKG在压力性钠尿中起重要作用，这一途径的缺陷导致盐敏感性和高血压。其具体目的是(1)验证RPT细胞内压力-钠尿是由细胞外RL-cGMP和细胞内PKG(I型)介导的假说；(2)检验盐敏感型高血压压力-钠尿抑制是由于细胞外RL-cGMP产生缺陷所致，而在自发性高血压则是由于RL-cGMP作用缺陷所致。特定目的的证据将确定和表征细胞外RL cGMP的新作用，并为高血压和其他与钠滞留相关的疾病状态提供潜在的治疗靶点。

项目成果

Reinforcing feedback loop of renal cyclic guanosine 3' 5' -monophosphate and interstitial hydrostatic pressure in pressure-natriuresis.

• DOI: 10.1161/hypertensionaha.109.131995
• 发表时间: 2009-12
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Lieb DC;Kemp BA;Howell NL;Gildea JJ;Carey RM
• 通讯作者: Carey RM

Extracellular renal guanosine cyclic 3'5'-monophosphate modulates nitric oxide and pressure-induced natriuresis.

细胞外肾鸟苷环 35-单磷酸调节一氧化氮和压力诱导的尿钠排泄。

• DOI: 10.1161/hypertensionaha.107.092973
• 发表时间: 2007
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Ahmed,Farah;Kemp,BrandonA;Howell,NancyL;Siragy,HelmyM;Carey,RobertM
• 通讯作者: Carey,RobertM

Intact microtubules are required for natriuretic responses to nitric oxide and increased renal perfusion pressure.

对一氧化氮的利尿钠反应和增加的肾灌注压需要完整的微管。

• DOI: 10.1161/hypertensionaha.107.103036
• 发表时间: 2008
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Park,Jennifer;Kemp,BrandonA;Howell,NancyL;Gildea,JohnJ;Keller,SusannaR;Carey,RobertM
• 通讯作者: Carey,RobertM