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

描述(申请人提供)：高血压(高血压)影响1/3的成年人，是心血管疾病和中风发展的独立危险因素。盐敏感型高血压在非裔美国人中很普遍，可归因于高血压的终末期肾病(ESRD)在非裔美国人中的发病率是白人的6倍。盐敏感型高血压的病因和导致高血压肾损害进展的因素仍然知之甚少。HV1(编码的HVCN1)是一种电压门控的H+通道，在细菌杀死免疫细胞的呼吸爆发过程中，最大限度地形成活性氧物种是必需的。最近的一些研究已经确定了Hv1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次将Hv1定位于肾脏，它出现在髓质厚升支(MTAL)的顶膜上。我们的假设是，Hv1通过促进肾单位段的Na+重吸收和促进活性氧物种的形成，促进了盐敏感型高血压和肾脏损伤的发展。我们推测，通过这些机制，Dahl盐敏感大鼠肾脏中Hv1活性的增强有助于该模型中高血压、氧化应激和肾脏损伤的发生。我们将在野生型Dahl盐敏感、耐盐和Hv1零突变Dahl盐敏感大鼠身上测试我们的假设。我们的假设得到了以下数据的支持：Hv1促进mTAL中活性氧的产生，Hv1有助于Dahl盐敏感大鼠的血压升高，以及Hv1的激活促进肾损伤的进展。我们的建议将检验以下假设：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Hv1活性的增强促进了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.