Epithelial Na channel (ENaC) polymorphisms in hyptertention

描述（由申请人提供）：血压部分通过调节远端肾单位的钠重吸收来控制。上皮钠通道（ENaC）的活性限制了钠的再吸收。醛固酮是肾素-血管紧张素-醛固酮系统（RAAS）中的最后一种激素，它能提高ENaC活性，从而升高血压。人类通过经典的负反馈机制控制血压，RAAS在血压下降时激活ENaC。所有形式的遗传性单基因高血压都与盐敏感性有关，并且是在血压升高时ENaC不适当激活的结果。这些严重但罕见的高血压疾病是由ENaC或其上游调节因子RAAS的功能突变引起的。更普遍但不那么严重的原发性高血压是一种多基因易感性的表现，这种易感性会因生活方式选择和环境因素而加剧血压升高。许多原发性高血压，尤其是非洲裔美国人，与盐敏感性和低肾素和醛固酮水平有关。由于负反馈调节，伴有盐敏感性、低肾素和醛固酮的高血压与ENaC功能障碍有关。分子遗传学研究确定了非洲裔美国人群体中富集ENaC的序列变异（多态性）。最近有人提出，非洲裔美国人群中普遍存在的四种ENaC多态性（alpha 334a、C618F、T663A和beta T594M）与低肾素/醛固酮高血压之间可能存在联系；然而，这些多态性对ENaC功能的影响仍有待检验。因此，尚不清楚这些多态性是否在某些形式的盐敏感性高血压中起致病作用。目前的建议通过测试ENaC多态性增加通道活性的假设来解决这个问题。我们的实验室有能力进行这项研究，因为我们有能力评估重组ENaC在哺乳动物表达系统中的功能。我们将利用这一专业知识来解决两个具体目标：1)确定ENaC多态性对通道活性的影响；2)确定多态ENaC增加活性的细胞/分子机制。初步结果支持这项调查的可行性，并表明这条调查路线将产生重大和新颖的发现。

DESCRIPTION (provided by applicant): Blood pressure is controlled, in part, by regulated sodium reabsorption at the distal renal nephron. Here, activity of the epithelial Na channel (ENaC) is limiting for sodium reabsorption. Aldosterone, the final hormone in the renin-angiotensin-aldosterone-system (RAAS), increases ENaC activity to increase blood pressure. Humans control blood pressure through a classic negative-feedback mechanism with RAAS activating ENaC as blood pressure falls. All forms of inheritable, monogenic hypertension are associated with salt-sensitivity and result from inappropriate activation of ENaC in the face of elevated blood pressure. These severe but rare hypertensive diseases result from either gain of function mutations in ENaC or its upstream regulator RAAS. The more prevalent but less severe essential hypertension is a manifestation of a polygenic predisposition towards elevated blood pressure exacerbated by life-style choices and environmental factors. Much essential hypertension particularly that in African American populations is associated with salt-sensitivity and low renin and aldosterone levels. Due to negative-feedback regulation, hypertension with salt-sensitivity, low renin and aldosterone implicates ENaC dysfunction. Molecular genetic studies identified sequence variations (polymorphisms) in ENaC enriched in African American populations. Possible linkage between four ENaC polymorphisms prevalent in African American populations, (alphaT334A, C618F, T663A and beta T594M) with low-renin/aldosterone hypertension has recently been suggested; however, the effects of these polymorphisms on ENaC function remain to be tested. Thus, it is unclear if these polymorphisms can play a causative role in some forms of salt-sensitive hypertension. The current proposal addresses this question by testing the hypothesis that ENaC polymorphisms increase channel activity. Our laboratory is well positioned to conduct this investigation for we are capable of assessing function of recombinant ENaC in a mammalian expression system. We will utilize this expertise to address two Specific Aims: 1) Determine the effects of ENaC polymorphisms on channel activity; and 2) Determine the cellular/molecular mechanisms by which polymorphic ENaC has increased activity. Preliminary results support the feasibility of this investigation and suggest that this line of inquiry will yield significant and novel findings.