Epithelial Na channel (ENaC) polymorphisms in hyptertention

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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.