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Regulation of NOS Activity in the Kidney & Hypertension

肾脏中 NOS 活性的调节

基本信息

批准号：
7595338
负责人：
Jeffrey L. Garvin
金额：
$ 37.66万
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/7595338
关键词：
1-Phosphatidylinositol 3-Kinase Affect Apyrase Arginine Autacoids Bicarbonates Binding Biochemical Blood Blood Pressure Blood Vessels Chelating Agents Cultured Cells Cyclic AMP Cyclic GMP Data Defect Dominant-Negative Mutation Endothelial Cells Enzymes Epithelial Cells Excretory function Hexoses Hypertension In Vitro Ions Kidney Knockout Mice Lead Limb structure Measures Mechanics Mediating Methods NOS3 gene Nitric Oxide Nitric Oxide Synthase Phosphotransferases Physiological Production Rattus Regulation Reporting Resistance Role Small Interfering RNA Sodium Chloride Stretching TRPV channel Testing Thick Vanilloid absorption blood pressure regulation human NOS3 protein hypertension treatment in vivo inhibitor/antagonist luminal membrane molecular imaging new therapeutic target novel phosphoric diester hydrolase pressure prevent receptor response salt sensitive shear stress sodium-potassium chloride cotransporter 2 protein

项目摘要

Nitric oxide (NO)reduces blood pressure by dilating blood vessels and promoting renal salt excretion. Thick ascending limbs absorb 30% of the filtered NaCI. Inappropriate salt retention by this segment leads to hypertension. We reported that NO produced by NO synthase (NOS) 3 in the thick ascending limb acts as an autacoid to inhibit transport. Flow augments NOS 3 activity via mechano-sensitive channels in endothelial cells. Our preliminary data show that luminal flow activates NOS 3 in thick ascending limbs and this requires translocation of the enzyme to the luminal membrane. However, it is not known how luminal flow regulates NOS 3 activity in this segment or how flow-induced NO affects NaCI reabsorption. We hypothesize that increasing luminal flow in thick ascending limbs stimulates NO production by NOS 3 via activation of mechano-sensitive TRPV4 channels, release of ATP and activation of Akt.The NO thus produced blunts NaCI reabsorption. Defects in the response to flow-stimulated NO production enhance salt retention and promote salt-sensitive hypertension. This hypothesis will be tested in 4 aims. Aim I. Hypothesis: Increasing luminal flow causes translocation and activation of NOS 3, stimulating NO production by the thick ascending limb due to increased shear stress. Aim II. Hypothesis: Luminal flow enhances NOS 3 activity by activating TRPV 4 channels and causing local increases in intracellular Ca. Aim III.Hypothesis: TRPV 4 activation by luminal flow induces release of ATP, which binds to purinergic 2 receptors and activates phosphatidylinositol 3 kinase, Akt and NOS 3. Aim IV: Hypothesis: Flow-stimulated NO production inhibits Na reabsorption by thick ascending limbs via activation of cGMP-stimulated phosphodiesterase 2 and reductions in cAMP. Defects in the response to flow-enhanced NO production promote salt retention and salt-sensitive hypertension. We will study how flow stimulates NO in perfused tubules and cultured cells using physiological, imaging, molecular and biochemical methods. Project 1 relates to the central theme since it will study renal NOS 3 regulation and the effects of NO on salt absorption. Information from Project 1 will be integrated with that from all other projects. It will use all of the cores. These will be the first studies to define how flow activates NOS 3, its effects on Na reabsorption by the thick ascending limb and whether these effects are blunted in salt-sensitive hypertension. This information may lead to new therapeutic targets for the treatment of hypertension.

一氧化氮（NO）通过扩张血管和促进肾盐排泄来降低血压。厚