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  • Review Article
  • Published:

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

Nature Reviews Nephrology volume 10, pages 146–157 (2014)Cite this article

Subjects

Key Points

  • Renal perfusion pressure, glomerular filtration and net renal sodium reabsorption maintain volume homeostasis

  • Cell stiffness and myogenic tone contribute to peripheral vascular resistance in the presence of aldosterone and normal sodium concentrations in the arterial circulation

  • Structural similarities exist between the amiloride-sensitive sodium channels in the epithelial and endothelial cells

  • Distinctions based on functional differences, especially in response to changes in extracellular sodium concentrations, might permit development of novel pharmacological approaches to differentially target epithelial and endothelial sodium channels

  • Agents that preferentially inhibit the vascular channels could lower systemic blood pressure without the associated inhibition of potassium secretion that accompanies the available sodium channel blockers and mineralocorticoid receptor antagonists

Abstract

Sodium transport in the distal nephron is mediated by epithelial sodium channel activity. Proteolytic processing of external domains and inhibition with increased sodium concentrations are important regulatory features of epithelial sodium channel complexes expressed in the distal nephron. By contrast, sodium channels expressed in the vascular system are activated by increased external sodium concentrations, which results in changes in the mechanical properties and function of endothelial cells. Mechanosensitivity and shear stress affect both epithelial and vascular sodium channel activity. Guyton's hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. The synergistic effects, and complementary regulation, of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and probably reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. In this Review, we focus on the expression and regulation of sodium channels, and we outline the emerging evidence that describes the central role of amiloride-sensitive sodium channels in the efferent (vascular) and afferent (epithelial) arms of this homeostatic system.

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Figure 1: Heteromeric architecture and subunit structure of ENaC.
Figure 2: Model of EnNaC-dependent transition from endothelial function to dysfunction.
Figure 3: Interactions between vascular endothelial cells and smooth muscle cells.

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Acknowledgements

We thank B. C. Rossier (University of Lausanne, Lausanne, Switzerland) for insightful comments made during the preparation of this Review. The authors are supported by grants from: the National Institutes of Health (DK051391, DK065161 and DK079307) and the Pittsburgh Centre for Kidney Research, T. R. Kleyman; Institut National pour la Santé et Recherche Médicale and the Agence Nationale pour la Recherche (ANR09-BLAN-0156-01), F. Jaisser; Deutsche Forschungsgemeinschaft (1496/4-1; KKU) and Koselleck grant (63/18), H. Oberleithner; the UAB/UCSD O'Brien Centre for Kidney Research (P30 DK079337), D. G. Warnock. H. Oberleithner and K. Kusche-Vihrog gratefully acknowledge the networking activities of EU-COST Action TD 1002 (AFM4NANOMED&BIO).

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, 34294-0007, AL, USA

    David G. Warnock

  2. Institut für Physiologie II, Westfälische Wilhelms Universität, Robert-Koch-Straße 27, Münster, 48149, Germany

    Kristina Kusche-Vihrog & Hans Oberleithner

  3. INSERM U872 Team 1, Centre de Recherche des Cordeliers, Université René Descartes, Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, 75006, France

    Antoine Tarjus & Frederic Jaisser

  4. Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, 15261, PA, USA

    Shaohu Sheng & Thomas R. Kleyman

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Contributions

D. G. Warnock, K. Kusche-Vihrog, A. Tarjus, S. Sheng, H. Oberleithner, T. R. Kleyman and F. Jaisser researched data for the article, contributed to writing the article and to review and/or editing of the manuscript before submission. D. G. Warnock, K. Kusche-Vihrog, H. Oberleithner, T. R. Kleyman and F. Jaisser provided a substantial contribution to discussions of the content. T. R. Kleyman and F. Jaisser contributed equally as senior authors of the manuscript.

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D. G. Warnock is a consultant for Gilead Sciences and Parion Sciences.

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Warnock, D., Kusche-Vihrog, K., Tarjus, A. et al. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells. Nat Rev Nephrol 10, 146–157 (2014). https://doi.org/10.1038/nrneph.2013.275

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