Regulation of ENaC in salt-sensitive hypertension via inflammation-induced ROS production

通过炎症诱导的 ROS 产生调节盐敏感性高血压中的 ENaC

基本信息

批准号：
9324063
负责人：
Tengis S Pavlov
金额：
$ 23.07万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-22 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324063
关键词：
Actin-Binding Protein Actins Address Aldosterone Amiloride Attenuated Biochemical Biomedical Research Blood Pressure Blood Vessels Blood Volume Cells Chronic Complex Consumption Cytoskeleton DNA Sequence Alteration Dahl Hypertensive Rats Data Development Disease Distal EMS1 gene Electrophysiology (science)Equilibrium Functional disorder Funding Gene-Modified Generations Genetic Goals Grant Health Homeostasis Hydrogen Peroxide Hypertension Immune Immune Cell Activation Individual Infiltration Inflammation Ion Channel Kidney Kidney Diseases Lead Liquid substance Lung Mediating Microscopic Mission Modeling Molecular Mutate NADPH Oxidase National Heart, Lung, and Blood Institute Neoplasm Metastasis Nephrons Organ Oxidative Stress Pathologic Pathway interactions Patients Physiology Play Positioning Attribute Production Protein Engineering Proteins Protocols documentation Publishing RAG1 gene Rat Strains Rat-1 Rattus Reactive Oxygen Species Regulation Research Resistance Role Signal Transduction Sodium Sodium Chloride Sodium-Restricted Diet Source Syndrome T-Lymphocyte Therapeutic immunosuppression Translating Tubular formation United States National Institutes of Health Water benzamil blood pressure regulation career clinical practice consomic disease phenotype epithelial Na+ channel experimental study high salt diet improved inhibitor/antagonist insight kidney cortex neglect neutrophil cytosol factor 67K normotensive respiratory response salt sensitive salt sensitive hypertension small hairpin RNA wasting

项目摘要

DESCRIPTION (provided by applicant): Epithelial sodium channel (ENaC) is a key regulator of sodium homeostasis in aldosterone-sensitive distal nephron (ASDN) controlling body liquid volume and blood pressure. Dysfunction and aberrant regulation of ENaC lead to a spectrum of diseases associated with abnormal sodium handling, ranging from hypo- to hypertension with sodium retention and wasting, respectively, to respiratory syndromes. The studies focused on the role of ENaC in normal and pathological physiology can be translated into clinical practice and fulfill the mission of NHLBI to improve health of the patients. Sodium loading is associated with an increase in blood pressure in normotensive and hypertensive individuals. Dahl salt-sensitive (SS) rats used in this proposal develop severe hypertension on high-salt diet. Our preliminary data indicate that ENaC-mediated Na+ reabsorption in the ASDN contributes to salt-sensitive hypertension in SS rat strain and I hypothesize here that excessive H2O2 production mediates this effect. ENaC subunits expression is inappropriately upregulated in SS rats fed a high salt diet compared to SS rats fed a low salt diet and consomic SS-13BN rats fed a high salt diet. Treatment with ENaC inhibitor benzamil attenuates increase in blood pressure in SS rats. Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of salt-sensitive hypertension in SS rats. Moreover, our preliminary results demonstrate that ENaC activity is upregulated by H2O2 production. I hypothesize that ENaC-mediated Na+ reabsorption in the ASDN plays a role in the development of salt-sensitive hypertension and that activation of immune cells increases generation of H2O2, which correspondingly activates ENaC and participates in the development of salt-sensitive hypertension. It is further hypothesized that increased H2O2 production results in changes of the actin cytoskeleton and that cortactin and MIM proteins are involved in this mechanism. Built upon our preliminary data and previously published findings, the specific objectives of this proposal are to determine whether infiltration increases H2O2 production in the kidney cortex and consequently upregulates ENaC-mediated sodium reabsorption in the ASDN and define the precise mechanisms of H2O2-mediated changes in ENaC activity. A combination of variety approaches will be used in this proposal to provide mechanistic insights on how ENaC is regulated by H2O2 and how changes in this pathway contribute to salt-induced hypertension. These studies will address two Specific Aims: 1) To determine if infiltration of T cells and consecutive H2O2 production in SS rats increases ENaC activity; 2) To define the cellular and molecular mechanism by which H2O2 modulates ENaC activity. My long-term professional goal is to continue my academic career in the field of biomedical research to study ion channels involved in regulation of salt and water balance at the cellular, organ and systemic levels. The K99/R00 grant fits to my career goals providing excellent opportunity to assist in transitioning to a stable independent research position with NIH or other independent research funding.

描述（由申请人提供）：上皮钠通道（ENAC）是醛固酮敏感的远端肾单位（ASDN）控制体液体体积和血压的关键调节剂。功能障碍和异常调节ENAC导致与异常钠处理相关的疾病，从低到高血压到高血压，分别保留钠和浪费，再到呼吸综合征。侧重于ENAC在正常生理和病理生理学中的作用的研究可以转化为临床实践，并履行NHLBI的使命，以改善患者的健康状况。钠负荷与正常性和高血压个体的血压升高有关。该提案中使用的DAHL盐敏感（SS）大鼠在高盐饮食时会出现严重的高血压。我们的初步数据表明，ASDN中的ENAC介导的Na+重吸收有助于SS大鼠菌株中盐敏感的高血压，而我在这里假设H2O2的过量产生介导了这种效应。与喂养低盐饮食的SS大鼠相比，在喂养高盐饮食的SS大鼠中，ENAC亚基表达不当上调。用ENAC抑制剂苯甲胺治疗SS大鼠的血压升高。肾脏中浸润的T淋巴细胞会增加氧化应激，并参与SS大鼠盐敏感性高血压的发展。此外，我们的初步结果表明，H2O2的产生使ENAC活性上调。我假设ASDN中的ENAC介导的Na+重吸收在盐敏感性高血压的发展中起作用，并且免疫细胞的激活增加了H2O2的产生，这相应地激活ENAC并参与盐敏感性高血压的发展。进一步假设，增加的H2O2产生会导致肌动蛋白细胞骨架的变化，并且Cortactin和Mim蛋白参与了该机制。基于我们的初步数据和先前发表的发现，该提案的具体目标是确定浸润是否会增加肾脏皮质中的H2O2产生，因此在ASDN中上调了ENAC介导的钠含量在ASDN中的吸收并定义了H2O2介导的ENAC活性变化的精确机制。该提案将使用多种方法的组合，以提供有关H2O2如何调节ENAC的机械见解，以及该途径的变化如何有助于盐引起的高血压。这些研究将解决两个具体目标：1）确定SS大鼠中T细胞和连续的H2O2产生的浸润是否会增加ENAC活性； 2）定义H2O2调节ENAC活性的细胞和分子机制。我的长期专业目标是继续我在生物医学研究领域的学术生涯，以研究涉及细胞，器官和全身水平的盐和水平衡调节的离子渠道。 K99/R00赠款符合我的职业目标，提供了绝佳的机会，可以协助过渡到 NIH或其他独立研究资金的稳定独立研究职位。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired epithelial Na+ channel activity contributes to cystogenesis and development of autosomal recessive polycystic kidney disease in PCK rats.

DOI：
10.1038/pr.2014.145
发表时间：
2015-01
期刊：
PEDIATRIC RESEARCH
影响因子：
3.6
作者：
Pavlov, Tengis S.;Levchenko, Vladislav;Ilatovskaya, Daria V.;Palygin, Oleg;Staruschenko, Alexander
通讯作者：
Staruschenko, Alexander

Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption.

Rho GDP 解离抑制剂 α 在控制上皮钠通道 (ENaC) 介导的钠重吸收中的作用。