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）是醛固酮敏感远端肾单位（ASDN）中钠稳态的关键调节剂，控制体液量和血压。 ENaC 的功能障碍和异常调节会导致一系列与钠处理异常相关的疾病，包括分别伴有钠潴留和消耗的低钠血症、高血压和呼吸综合征。重点关注 ENaC 在正常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 改善患者健康的使命。钠负荷与血压正常和高血压个体的血压升高有关。本提案中使用的 Dahl 盐敏感 (SS) 大鼠在高盐饮食下会出现严重高血压。我们的初步数据表明，ASDN 中 ENaC 介导的 Na+ 重吸收有助于 SS 大鼠品系的盐敏感性高血压，我在此假设过量的 H2O2 产生介导了这种效应。与饲喂低盐饮食的 SS 大鼠和饲喂高盐饮食的体质 SS-13BN 大鼠相比，饲喂高盐饮食的 SS 大鼠的 ENaC 亚基表达不适当上调。用 ENaC 抑制剂苯扎米尔治疗可减轻 SS 大鼠血压的升高。 SS 大鼠肾脏中的浸润性 T 淋巴细胞会增加氧化应激并参与盐敏感性高血压的发生。此外，我们的初步结果表明 ENaC 活性会因 H2O2 的产生而上调。我推测 ASDN 中 ENaC 介导的 Na+ 重吸收在盐敏感性高血压的发生中发挥作用，并且免疫细胞的激活增加了 H2O2 的产生，从而相应地激活 ENaC 并参与盐敏感性高血压的发生。进一步假设，H2O2 产生的增加会导致肌动蛋白细胞骨架的变化，并且 Cortactin 和 MIM 蛋白参与了这一机制。基于我们的初步数据和之前发表的研究结果，该提案的具体目标是确定渗透是否会增加肾皮质中 H2O2 的产生，从而上调 ASDN 中 ENaC 介导的钠重吸收，并定义 H2O2 介导的钠重吸收变化的精确机制。 ENaC 活性。该提案将结合使用多种方法，以提供关于 H2O2 如何调节 ENaC 以及该途径的变化如何导致盐诱发高血压的机制见解。这些研究将解决两个具体目标：1) 确定 SS 大鼠中 T 细胞的浸润和连续 H2O2 的产生是否会增加 ENaC 活性； 2) 定义H2O2调节ENaC活性的细胞和分子机制。我的长期职业目标是继续我在生物医学研究领域的学术生涯，研究参与细胞、器官和系统水平的盐和水平衡调节的离子通道。 K99/R00 补助金符合我的职业目标，提供了绝佳的机会来协助我过渡到获得 NIH 或其他独立研究资助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。