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      ENaC in Salt-Sensitive Hypertension: Kidney and Beyond

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose of Review

          The main goal of this article is to discuss the role of the epithelial sodium channel (ENaC) in extracellular fluid and blood pressure regulation.

          Recent Findings

          Besides its role in sodium handling in the kidney, recent studies have found that ENaC expressed in other cells including immune cells can influence blood pressure via extra-renal mechanisms. Dendritic cells (DCs) are activated and contribute to salt-sensitive hypertension in an ENaC-dependent manner. We discuss recent studies on how ENaC is regulated in both the kidney and other sites including the vascular smooth muscles, endothelial cells, and immune cells. We also discuss how this extra-renal ENaC can play a role in salt-sensitive hypertension and its promise as a novel therapeutic target.

          Summary

          The role of ENaC in blood pressure regulation in the kidney has been well studied. Recent human gene sequencing efforts have identified thousands of variants among the genes encoding ENaC, and research efforts to determine if these variants and their expression in extra-renal tissue play a role in hypertension will advance our understanding of the pathogenesis of ENaC-mediated cardiovascular disease and lead to novel therapeutic targets.

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          Most cited references113

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          Targeting Toll-like receptors: emerging therapeutics?

          Elizabeth J Hennessy, Andrew Parker, Luke A J O'Neill (2010)
          There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.
          Article 0 comments Cited 275 times – based on 0 reviews     Review now
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            Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.

            C M Canessa, L Schild, G. Buell … (1994)
            The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
            Article 0 comments Cited 258 times – based on 0 reviews     Review now
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              Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction.

              Meena S Madhur, Heinrich E. Lob, Louise A. McCann … (2010)
              We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.
              Article 0 comments Cited 248 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Annet Kirabo: annet.kirabo@vanderbilt.edu
                Journal
                Journal ID (nlm-ta): Curr Hypertens Rep
                Journal ID (iso-abbrev): Curr. Hypertens. Rep
                Title: Current Hypertension Reports
                Publisher: Springer US (New York )
                ISSN (Print): 1522-6417
                ISSN (Electronic): 1534-3111
                Publication date (Electronic): 27 August 2020
                Publication date PMC-release: 27 August 2020
                Publication date (Print): 2020
                Volume: 22
                Issue: 9
                Electronic Location Identifier: 69
                Affiliations
                [1 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Division of Clinical Pharmacology, Department of Medicine, , Vanderbilt University Medical Center, ; 2215 Garland Avenue, P415C Medical Research Building IV, Nashville, TN 37232 USA
                [2 ]GRID grid.152326.1, ISNI 0000 0001 2264 7217, Department of Molecular Physiology and Biophysics, , Vanderbilt University, ; Nashville, TN USA
                [3 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Departments of Medicine, Cell Biology, Pharmacology, and Chemical Biology, , University of Pittsburgh, ; Pittsburgh, PA USA
                Article
                Publisher ID: 1067
                DOI: 10.1007/s11906-020-01067-9
                PMC ID: 7452925
                PubMed ID: 32852643
                SO-VID: 021c4233-927d-475e-8306-04288b0367e6
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Categories
                Subject: Inflammation and Cardiovascular Diseases (A Kirabo, Section Editor)
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media, LLC, part of Springer Nature 2020

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: enac,hypertension,inflammation,sodium
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: enac, hypertension, inflammation, sodium

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