Angiotensin II increases activity of the epithelial Na + channel (ENaC) in distal nephron additively to aldosterone

Mykola Mamenko, Oleg Zaika, Daria V. Ilatovskaya, Alexander Staruschenko, Oleh Pochynyuk

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Dietary salt intake controls epithelial Na + channel (ENaC)-mediated Na + reabsorption in the distal nephron by affecting status of the renin-angiotensin-aldosterone system (RAAS). Whereas regulation of ENaC by aldosterone is generally accepted, little is known about whether other components of RAAS, such as angiotensin II (Ang II), have nonredundant to aldosterone-stimulatory actions on ENaC. We combined patch clamp electrophysiology and immunohistochemistry in freshly isolated split-opened distal nephrons of mice to determine the mechanism and molecular signaling pathway of Ang II regulation of ENaC. We found that Ang II acutely increases ENaC P o, whereas prolonged exposure to Ang II also induces translocation of α-ENaC toward the apical membrane in situ. Ang II actions on ENaC P o persist in the presence of saturated mineralocorticoid status. Moreover, aldosterone fails to stimulate ENaC acutely, suggesting that Ang II and aldosterone have different time frames of ENaC activation. AT 1 but not AT 2 receptors mediate Ang II actions on ENaC. Unlike its effect in vasculature, Ang II did not increase [Ca 2+] i in split-opened distal nephrons as demonstrated using ratiometric Fura-2-based microscopy. However, application of Ang II to mpkCCD c14 cells resulted in generation of reactive oxygen species, as probed with fluorescent methods. Consistently, inhibiting NADPH oxidase with apocynin abolished Ang II-mediated increases in ENaC P oin murine distal nephron. Therefore, we concluded that Ang II directly regulates ENaC activity in the distal nephron, and this effect complements regulation of ENaC by aldosterone.We ropose that stimulation of AT 1 receptors with subsequent activation of NADPH oxidase signaling pathway mediates Ang II actions on ENaC.

Original languageEnglish (US)
Pages (from-to)660-671
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number1
DOIs
StatePublished - Jan 2 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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