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

• 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
• 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

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（高血压）影响3人中的1人，是心血管疾病和中风发展的独立危险因素。在非洲裔美国人中，对盐敏感的高血压普遍存在，与白人相比，非裔美国人的高血压末期末期肾脏疾病（ESRD）的发生率高6倍。盐敏感性高血压的病因以及导致高血压肾脏损伤进展的因素仍然很少了解。 HV1（编码HVCN1）是一种电压门控的H+通道，在细菌杀死免疫细胞中杀死呼吸道爆发期间，最大活性氧形成所必需。许多最近的研究已经确定了HV1在包括肺和精子在内的非免疫组织中的作用。我们引人注目的初步数据是第一个将HV1定位到肾脏的数据，它的呈现在髓质较厚的上升肢（MTAL）的顶部膜上。我们的假设是，HV1通过增强该肾单位段中的Na+重吸收并促进活性氧形成，从而有助于盐敏感高血压和肾脏损伤的发展。我们假设通过这些机制，在DAHL盐敏感大鼠肾脏中HV1的活性增强了该模型中高血压，氧化应激和肾损伤的发展。我们将在野生型DAHL盐敏感，耐盐和HV1无盐的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，表明HV1促进了MTAL中的活性氧的产生，HV1有助于DAHL盐敏感大鼠的血压升高，而HV1激活促进了肾脏损伤的进展。 +“ - 在我们的提案中将测试假设：1）通过HV1通过HV1通过NADPH氧化酶驱动O2的O2驱动O2; 2）MTAL中的HV1活性增强了MTAL中的Na +吸收MTAL中的Na +吸收; 3）增强DAHL盐敏感大鼠中HV1的HV1活性促进了这些动物中肾脏疾病的进展。