Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation

Mykola Mamenko, Oleg Zaika, Minolfa C. Prieto, V. Behrana Jensen, Peter A. Doris, L. Gabriel Navar, Oleh Pochynyuk

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron. We used freshly isolated aldosterone-sensitive distal nephron from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC, but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than 2 times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the aldosterone-sensitive distal nephron. In contrast, in the setting of Ang II-dependent hypertension, ENaC activity is upregulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels.

Original languageEnglish (US)
Pages (from-to)1111-1122
Number of pages12
JournalHypertension
Volume62
Issue number6
DOIs
Publication statusPublished - Sep 26 2013
Externally publishedYes

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Keywords

  • Collecting duct
  • Hypertension
  • Nephrons

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Mamenko, M., Zaika, O., Prieto, M. C., Behrana Jensen, V., Doris, P. A., Gabriel Navar, L., & Pochynyuk, O. (2013). Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation. Hypertension, 62(6), 1111-1122. https://doi.org/10.1161/HYPERTENSIONAHA.113.01797