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

描述（由申请人提供）：高血压（高血压）影响三分之一的成年人，是心血管疾病和中风发展的独立风险因素。盐敏感性高血压在非裔美国人中很普遍，与白人相比，非裔美国人中高血压导致的终末期肾病（ESRD）的发病率高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然知之甚少。Hv 1（编码HVCN 1）是一种电压门控H+通道，其在免疫细胞中的细菌杀伤呼吸爆发期间为最大活性氧形成所需。最近的一些研究已经确定了Hv 1在非免疫组织中的作用，包括在肺和精子中。我们令人信服的初步数据是第一个本地化Hv 1的肾脏，在那里它存在于髓厚升支（mTAL）的顶膜。我们的假设是，Hv 1有助于盐敏感性高血压和肾损伤的发展，既通过增强Na+重吸收在这一肾单位段，并通过促进活性氧的形成。我们推测，通过这些机制，增加活动的Hv 1在达尔盐敏感大鼠的肾脏有助于发展高血压，氧化应激和肾损伤在这个模型中。我们将测试我们的假设在野生型达尔盐敏感，耐盐和Hv 1无效突变达尔盐敏感大鼠。我们的假设是支持的数据表明，Hv 1促进活性氧在mTAL的生产，Hv 1有助于血压升高达尔盐敏感大鼠，和Hv 1激活促进肾损伤的进展。在我们的提议中将检验+“-以下假设：1）通过Hv 1的H流出驱动NADPH氧化酶产生O2; 2）mTAL中的Hv 1活性增强mTAL中的Na+重吸收; 3）Dahl盐敏感大鼠中Hv 1活性增强促进这些动物肾脏疾病的进展。

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.