Role of HV1 in development of salt-sensitive hypertension and renal injury

HV1 在盐敏感性高血压和肾损伤发展中的作用

基本信息

批准号：
8758494
负责人：
Paul Michael O'Connor
金额：
$ 30.22万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-03-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758494
关键词：
Acidosis Acids Adult Affect African American Animals Apical Automobile Driving Blood Pressure Cardiovascular Diseases Cells Chronic Kidney Failure Dahl Hypertensive Rats Data Development Diet Disease Disease Progression End stage renal failure Epidemic Etiology Functional disorder Genetic Glomerular Filtration Rate Goals Hypertension Imaging Techniques Immune Incidence Individual Injury Injury to Kidney Intake Ion Channel KCNJ1 gene Kidney Kidney Diseases Knowledge Lead Limb structure Lung Maintenance Mediating Mediator of activation protein Membrane Metabolic acidosis Modeling Molecular Target NADPH Oxidase Nephrons Operative Surgical Procedures Outcome Oxidases Oxidative Stress Pathway interactions Physiological Physiology Predisposition Production Protons Rattus Reactive Oxygen Species Recycling Renal Hypertension Resistance Respiratory Burst Risk Factors Role Simulate Sodium Chloride Stimulus Stroke Superoxides Testing Thick Tissues Tubular formation apical membrane clinical practice feeding in vivo killings molecular imaging mutant novel prevent public health relevance response salt sensitive salt sensitive hypertension sperm cell symporter voltage

项目摘要

DESCRIPTION (provided by applicant): Hypertension (High blood pressure) affects 1 in 3 adults and is an independent risk factor for the development of cardiovascular disease and stroke. Salt-sensitive hypertension is prevalent in African Americans and the incidence of end-stage renal disease (ESRD) attributable to hypertension is 6-fold higher in African Americans when compared to whites. The etiology of salt-sensitive hypertension and the factors that lead to progression of hypertensive kidney injury remain poorly understood. Hv1 (encoded HVCN1) is a voltage-gated H+ channel which is required for maximal reactive oxygen species formation during the bacterial killing respiratory burst in immune cells. A number of recent studies have identified a role of Hv1 in non-immune tissues, including in the lung and spermatozoa. Our compelling preliminary data are the first to localize Hv1 to the kidney, where it its present on th apical membrane of medullary thick ascending limb (mTAL). Our hypothesis is that Hv1 contributes to the development of salt-sensitive hypertension and renal injury both by enhancing Na+ reabsorption in this nephron segment and by promoting reactive oxygen species formation. We hypothesize that through these mechanisms, augmented activity of Hv1 in the kidney of Dahl salt-sensitive rats contributes to the development of hypertension, oxidative stress and renal injury in this model. We will test our hypothesis in wild-type Dahl salt-sensitive, salt-resistant and Hv1 null-mutant Dahl salt-sensitive rats. Our hypothesis is supported by data indicating that Hv1 promotes reactive oxygen species production in mTAL, that Hv1 contributes to blood pressure elevation in Dahl salt-sensitive rats, and that Hv1 activation promotes the progression of renal injury. The + "- following hypothesis will be tested in our proposal: 1) H efflux via Hv1 drives O2 production by NADPH oxidase; 2) Hv1 activity in mTAL enhances Na+ reabsorption in mTAL; 3) Augmented Hv1 activity in Dahl salt-sensitive rats promotes the progression of renal disease in these animals.

描述（由申请人提供）：高血压影响三分之一的成年人，是发生心血管疾病和中风的独立危险因素。盐敏感性高血压在非裔美国人中普遍存在，与白人相比，非裔美国人因高血压导致的终末期肾病 (ESRD) 的发病率高出 6 倍。盐敏感性高血压的病因和导致高血压肾损伤进展的因素仍知之甚少。 Hv1（编码为 HVCN1）是一种电压门控 H+ 通道，在免疫细胞杀灭细菌的呼吸爆发过程中，它是形成最大活性氧物质所必需的。最近的许多研究已经确定了 Hv1 在非免疫组织中的作用，包括肺和精子。我们令人信服的初步数据首次将 Hv1 定位于肾脏，它存在于髓质厚升肢 (mTAL) 的顶膜上。我们的假设是，Hv1 通过增强该肾单位段的 Na+ 重吸收和促进活性氧的形成，从而导致盐敏感性高血压和肾损伤的发生。我们推测，通过这些机制，Dahl 盐敏感大鼠肾脏中 Hv1 的活性增强有助于该模型中高血压、氧化应激和肾损伤的发生。我们将在野生型 Dahl 盐敏感大鼠、盐抗性大鼠和 Hv1 无效突变 Dahl 盐敏感大鼠中检验我们的假设。我们的假设得到了数据的支持，这些数据表明 Hv1 促进 mTAL 中活性氧的产生，Hv1 导致 Dahl 盐敏感大鼠血压升高，并且 Hv1 激活促进肾损伤的进展。我们的提案将检验以下假设：1) 通过 Hv1 的 H 外流驱动 NADPH 氧化酶产生 O2；2) mTAL 中的 Hv1 活性增强 mTAL 中的 Na+ 重吸收；3) Dahl 盐敏感大鼠中增强的 Hv1 活性促进这些动物肾脏疾病的进展。