Epithelial Na channel (ENaC) polymorphisms in hyptertention

描述（由申请人提供）：血压部分通过远端肾单位的钠重吸收调节来控制。在这里，上皮Na通道（ENaC）的活性限制钠重吸收。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，可增加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，当血压福尔斯下降时，RAAS激活ENaC。所有形式的遗传性单基因高血压都与盐敏感性相关，并且是由于面对血压升高时ENaC的不适当激活所致。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。原发性高血压更为普遍，但不太严重，这是一种多基因易感性的表现，生活方式的选择和环境因素加剧了血压升高。许多原发性高血压，特别是非洲裔美国人的原发性高血压与盐敏感性和低肾素和醛固酮水平有关。由于负反馈调节，高血压伴盐敏感性、低肾素和低醛固酮与ENaC功能障碍有关。分子遗传学研究确定了在非洲裔美国人人群中富集的ENaC序列变异（多态性）。最近提出了在非洲裔美国人人群中普遍存在的四种ENaC多态性（α T334 A、C618 F、T663 A和β T594 M）与低肾素/醛固酮高血压之间的可能联系;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。目前的建议解决了这个问题，通过测试的假设，ENaC多态性增加通道活动。我们的实验室是很好的定位进行这项研究，因为我们能够评估重组ENaC在哺乳动物表达系统中的功能。我们将利用这些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）确定多态性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.