Epithelial sodium channel (ENaC) is a key regulator of sodium homeostasis in aldosterone-sensitive distal nephron (ASDN) controlling body liquid volume and blood pressure. Dysfunction and aberrant regulation of ENaC lead to a spectrum of diseases associated with abnormal sodium handling, ranging from hypo- to hypertension with sodium retention and wasting, respectively, to respiratory syndromes. The studies focused on the role of ENaC in normal and pathological physiology can be translated into clinical practice and fulfill the mission of NHLBI to improve health of the patients. Sodium loading is associated with an increase in blood pressure in normotensive and hypertensive individuals. Dahl salt-sensitive (SS) rats used in this proposal develop severe hypertension on high-salt diet. Our preliminary data indicate that ENaC-mediated Na+ reabsorption in the ASDN contributes to salt-sensitive hypertension in SS rat strain and I hypothesize here that excessive H2O2 production mediates this effect. ENaC subunits expression is inappropriately upregulated in SS rats fed a high salt diet compared to SS rats fed a low salt diet and consomic SS-13BN rats fed a high salt diet. Treatment with ENaC inhibitor benzamil attenuates increase in blood pressure in SS rats. Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of salt-sensitive hypertension in SS rats. Moreover, our preliminary results demonstrate that ENaC activity is upregulated by H2O2 production. I hypothesize that ENaC-mediated Na+ reabsorption in the ASDN plays a role in the development of salt-sensitive hypertension and that activation of immune cells increases generation of H2O2, which correspondingly activates ENaC and participates in the development of salt-sensitive hypertension. It is further hypothesized that increased H2O2 production results in changes of the actin cytoskeleton and that cortactin and MIM proteins are involved in this mechanism. Built upon our preliminary data and previously published findings, the specific objectives of this proposal are to determine whether infiltration increases H2O2 production in the kidney cortex and consequently upregulates ENaC-mediated sodium reabsorption in the ASDN and define the precise mechanisms of H2O2-mediated changes in ENaC activity. A combination of variety approaches will be used in this proposal to provide mechanistic insights on how ENaC is regulated by H2O2 and how changes in this pathway contribute to salt-induced hypertension. These studies will address two Specific Aims: 1) To determine if infiltration of T cells and consecutive H2O2 production in SS rats increases ENaC activity;2) To define the cellular and molecular mechanism by which H2O2 modulates ENaC activity. My long-term professional goal is to continue my academic career in the field of biomedical research to study ion channels involved in regulation of salt and water balance at the cellular, organ and systemic levels. The K99/R00 grant fits to my career goals providing excellent opportunity to assist in transitioning to a stable independent research position with NIH or other independent research funding.

Public Health Relevance

The control of blood pressure occurs via Na+ homeostasis in the kidney and involves the precise regulation of the Epithelial Na+ Channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). The current proposal will study the role of inflammation in the kidney in the development of hypertension. Anticipated results will help to understand how to manage high blood pressure induced by high salt consumption.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (M2))
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Carlson, Drew E
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Medical College of Wisconsin
Schools of Medicine
United States
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Hye Khan, Md Abdul; Pavlov, Tengis S; Christain, Sarah V et al. (2014) Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 127:463-74
Pavlov, Tengis S; Levchenko, Vladislav; Staruschenko, Alexander (2014) Role of Rho GDP dissociation inhibitor ? in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption. J Biol Chem 289:28651-9