Blood Pressure Regulation: Novel Roles for the Kidney

血压调节：肾脏的新作用

基本信息

批准号：
8235821
负责人：
Pablo A. Ortiz
金额：
$ 205.44万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235821
关键词：
Achievement Acute Adenylate Cyclase Antihypertensive Agents Biliverdine Blood Pressure Blood Vessels Calcium-Sensing Receptors Carbon Monoxide Cardiac Cells Chronic Collaborations Cyclic AMP Cyclic GMP Dahl Hypertensive Rats Defect Doctor of Medicine Doctor of Philosophy Endocrine Endothelial Cells Epithelial Excretory function Feedback Functional disorder Funding Goals Grant Heme Hormones Hypertension Image In Vitro Individual Interdisciplinary Study Juxtaglomerular Cell Kidney Knowledge Knowledge acquisition Lead Limb structure Macula densa Mediating Microcirculation Modeling Molecular Biology Mus Nephrons Nitric Oxide Organ Oxygenases Play Process Production Program Research Project Grants Regulation Renal function Renin Research Research Activity Research Personnel Role Scientist Signal Transduction Smooth Muscle Myocytes Sodium Chloride Superoxides Testing Thick Tissues Vascular resistance Water Work autocrine blood pressure regulation extracellular hemodynamics human NOS3 protein in vivo interdisciplinary approach interest interstitial cell kidney vascular structure member multidisciplinary novel paracrine phosphodiesterase V phosphoric diester hydrolase programs response salt sensitive

项目摘要

DESCRIPTION (provided by applicant): This is a revised Program Project Grant, the central theme is that "endocrine, paracrine and autoerine factors produced by the epithelial, vascular smooth muscle, endothelial and interstitial cells play an important role in regulating salt and water excretion by the kidney, and thus blood pressure, by altering renal hempdynamics, changing NaCI reabsorption and mediating cross-talk between cells." The central hypothesis to be tested is that blood pressure regulation by the kidney occurs via integration of the actions of prch and anti-hypertensive agents on nephron transport, renal vascular resistance, release of renal hormones and cross-talk between epithelial and vascular cells. Defects in the integration process and/or actions of pro- and anti-hypertensive agents lead to renal dysfunction, salt retention and hypertension. This hypothesis will be tested in four projects that break new ground in our understanding of how the kidney regulates blood pressure. Project 1 will study whether increasing luminal flow in the thick ascending limb stimulates nitric oxide (NO) production by NO synthase 3, the signaling cascades involved, the effects of flow-induced NO on NaCI reabsorption, and whether a defective response to flow-stimulated NO production enhances sait retention and promotes salt-sensitive hypertension. Project 2 will test whether NO inhibits thick ascending limb NaCI reabsorption by activating cGMP-stimulated phosphodiesterase 2 (PDE2), reducing cAMP, and thus decreasing Na/K/2CI cotransport. It will also test in Dahl salt-sensitive rats whether a reduction in NOinduced inhibition of NaCI reabsorption and hypertension is caused by diminished PDE2 activity and enhanced cGMP degradation by phosphodiesterase 5. Project 3 will test whether heme oxygenases in the macula densa produce carbon monoxide (CO) and biliverdin, which act synergistically and in an autocrine manner to inhibit tubuloglomeailar feedback. It will also test whether CO acts by stimulating cGMP which inhibits Na/K/2CI cotransport, and blocks ATP release and biliverdin acts by decreasing superoxide, thereby increasing NO. Project 4 will test whether increased extracellular Ca inhibits renin release by activating Ca sensing receptors on juxtaglomerular cells which increases intracellular Ca and reduces cAMP production by inhibiting adenylyl cyclase-V and stimulating phosphodiesterase 1. These studies will be performed in vitro at the subcellular, cellular, and isolated tissue levels and in vivo using both acute and chronic models, and genetically manipulated mice. The four projects will be supported by three core units (Administrative, Molecular Biology and Analytical, and Imaging) that will facilitate the scientific effort. The Program Project Grant will provide integration of our efforts, continued collaboration and shared ideas and expertise. Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs.

描述（由申请人提供）： This is a revised Program Project Grant, the central theme is that "endocrine, paracrine and autoerine factors produced by the epithelial, vascular smooth muscle, endothelial and interstitial cells play an important role in regulating salt and water excretion by the kidney, and thus blood pressure, by altering renal hempdynamics, changing NaCI reabsorption and mediating cross-talk between cells."要测试的中心假设是，肾脏调节血压是通过整合PRCH和抗高血压剂对肾脏转运，肾血管耐药性，肾血管抗性，肾激素的释放以及上皮细胞和血管细胞之间的串扰而发生的。积分过程中的缺陷和/或抗高血压剂的作用导致肾功能障碍，盐保留和高血压。该假设将在我们对肾脏如何调节血压的理解中的四个项目中进行检验。项目1将研究厚升肢中的腔流量增加是否会刺激一氧化氮（NO）生产，NO合酶3，涉及的信号传导级联，流量引起的NO对NACI吸收吸收的影响以及对流动刺激的有缺陷响应是否会增强sait sait sait sait sait sait sait sait sait sait sait sait，并促进了盐敏感的高度。项目2将通过激活CGMP刺激的磷酸二酯酶2（PDE2），减少cAMP，从而降低Na/k/2CI共晶型，测试NO是否抑制了较厚的肢体NACI重吸收。 It will also test in Dahl salt-sensitive rats whether a reduction in NOinduced inhibition of NaCI reabsorption and hypertension is caused by diminished PDE2 activity and enhanced cGMP degradation by phosphodiesterase 5. Project 3 will test whether heme oxygenases in the macula densa produce carbon monoxide (CO) and biliverdin, which act synergistically and in an autocrine manner to抑制肾小管乳糖反馈。它还将通过刺激抑制Na/k/2ci共横向运动的CGMP来测试CO的作用，并通过减少超氧化物来阻止ATP释放和biliverdin作用，从而增加NO。项目4将测试增加的细胞外Ca是否通过激活链状细胞上的Ca感应受体来抑制肾素的释放，从而增加细胞内Ca并通过抑制腺苷酸环酶V并刺激磷酸二酯酶1来减少cAMC的产生。操纵小鼠。这四个项目将得到三个核心单元（行政，分子生物学以及分析和成像）的支持，这将有助于科学努力。计划项目赠款将提供我们的努力，持续协作以及共享思想和专业知识的整合。因此，它将加速肾脏调节血压的新机制知识的获取，并可能为抗高血压药物提供新的靶标。