Role of Thick Ascending Limb Free Radicals in Angiotensin II-Dependent Hyperten

粗升肢自由基在血管紧张素 II 依赖性高血压中的作用

基本信息

批准号：
7896552
负责人：
Jeffrey L. Garvin
金额：
$ 27.7万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7896552
关键词：
Address Affect Agonist Angiotensin II Angiotensins Animals Autacoids Biostatistics Core Blood Pressure Cardiac Co-Immunoprecipitations Data Data Analyses Dependency Development Diuresis Doctor of Medicine Doctor of Philosophy Dominant-Negative Mutation Dose Eicosanoids Endocrine Enzymes Equilibrium Excretory function Factor Analysis Free Radicals Heart Heart Hypertrophy Human Resources Hypertension Individual Inflammation Infusion procedures Kidney Kinins Knockout Mice Lead Limb structure Measures Mediating Mediation Modeling Mutant Strains Mice NADPH Oxidase Natriuresis Natriuretic Factors Nitric Oxide Nitric Oxide Synthase Organ Phosphoric Monoester Hydrolases Phosphorylation Play Principal Investigator Process Production Program Research Project Grants Protein Isoforms Protein Kinase C Protein phosphatase Rattus Reactive Oxygen Species Regulation Renal Hypertension Renal function Research Design Research Personnel Resistance Role Serine Signal Transduction Site Sodium Sodium Chloride Superoxides System Testing Therapeutic Effect Thick Threonine Tumor Necrosis Factor-alpha Tumor Necrosis Factors Water Western Blotting Wild Type Mouse Work Yang absorption abstracting acetovanillone arteriole autocrine base blood pressure regulation citrate carrier cyclooxygenase 2 human CYBA protein human NOS3 protein luminal membrane mutant neutrophil cytosol factor 67K normotensive paracrine prevent programs protective effect receptor salt intake saluretic

项目摘要

Principal Investigator/Program Director (Last, First, Middle): Garvin, Jeffrey L, Ph.D./CaiTeterO, Oscar A., M.D. PROJECT V Role of Thick Ascending Limb Free Radicals in Angiotensin ll-lnduced Hypertension Project Investigator: Jeffrey L. Garvin, Ph.D. Co-Investigator: Pablo A. Ortiz, Ph.D. Co-Investigator: Patrick J. Pagano, Ph.D. Co-Investigator: Xiao-Ping Yang, M.D. Abstract There is a balance between factors promoting renal salt and water excretion [i.e., nitric oxide (NO)] and those favoring retention [i.e., superoxide (O2")]. In angiotensin II (Ang Independent hypertension and other forms, this balance favors the latter. Inappropriate salt retention by the kidney may lead or contribute to Ang II- dependent hypertension. The thick ascending limb absorbs 20-30% of the filtered NaCI load. We have shown that NO specifically produced by endothelial or type 3 NO synthase (eNOS) in the thick ascending limb acts as an autacoid, inhibiting NaCI absorption, and may thereby contribute significantly to salt and water excretion. We have also shown that O2" stimulates NaCI absorption in the thick ascending limb. Ang ll-induced hypertension caused by infusion of low to moderate doses of Ang II is dependent on salt intake. These data indicate a significant role of the kidney in this form of hypertension. During Ang ll-induced hypertension renal cortical eNOS expression is enhanced, but our data show that medullary thick ascending limb expression decreases. In contrast, production of reactive oxygen species (including O2") is elevated in both regions. Currently, it is unclear how Ang ll-induced hypertension affects net NaCI absorption by the medullary thick ascending limb, or whether these effects are mediated by changes in NO and O2~ production. Thus we hypothesize that during Ang ll-induced hypertension there is a shift in the balance between the natriuretic factor NOand the antinatriuretic factor O2'in the thick ascending limb that favors the latter and enhances salt absorption. Aim I. Hypothesis: Ang ll-induced hypertension diminishes NOproduction in the thick ascending limb in part by reducing eNOS expression via release of tumor necrosis factor a (TNF a). Aim II. Hypothesis: Agonist-induced eNOS activation is reduced in Ang ll-induced hypertension due to increased phosphorylation at the inhibitory

首席研究员/计划主管（最后，第一，中间）：Garvin，Jeffrey L，博士学位/Caitetero，Oscar A.，M.D。项目v 血管紧张素ll-LNDNDDS的高血压中厚肢体自由基的作用项目调查员：Jeffrey L. Garvin博士共同投资者：Pablo A. Ortiz博士共同研究员：Patrick J. Pagano博士共同投资者：小亨Yang，医学博士抽象的促进肾脏盐和排泄的因素之间存在平衡[即一氧化氮（NO）]和那些有利于保留的人[即超氧化物（O2“）。在血管紧张素II（ANG独立的高血压和其他形式，这种平衡有利于后者。肾脏的不适当盐保留可能会导致或导致ANG II- 依赖性高血压。较厚的上升肢体吸收了20-30％的过滤Naci负载。我们已经显示了在厚的肢体中没有内皮或3型无合酶（ENOS）专门产生一种自闭症，抑制NACI的吸收，因此可能对盐和水排泄显着贡献。我们还表明，o2“刺激厚的升节中的NACI吸收。ang ll诱导由低至中等剂量的ANG II输注引起的高血压取决于盐的摄入。这些数据表明肾脏在这种高血压形式中的重要作用。在ANG LL诱导的高血压肾脏期间皮质eNOS表达增强减少。相反，两个区域的活性氧（包括O2”）的产生均升高。目前，目前尚不清楚ANG LL诱导的高血压如何影响髓质厚的NACI吸收上升的肢体，或这些影响是否是由NO和O2〜产生的变化介导的。因此我们假设在ANG LL引起的高血压期间，平衡发生了变化 NATRIEATIC因子NOAND抗钠尿素因子O2'IN厚的升节，有利于后者并增强盐的吸收。 AIM I.假设：ANG LL诱导的高血压减少通过释放肿瘤坏死因子A（TNF A）来减少eNOS表达，部分通过降低eNOS表达。目标II。假设：激动剂诱导的eNOS激活在ANG LL诱导的高血压中降低抑制性磷酸化增加