Faculty Collaboration Database

Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J Biol Chem 2012 Jan 02;287(1):660-671

Date

11/17/2011

Pubmed ID

22086923

Pubmed Central ID

PMC3249120

DOI

10.1074/jbc.M111.298919

Scopus ID

2-s2.0-84855282420 (requires institutional sign-in at Scopus site)   123 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 Po, whereas prolonged exposure to Ang II also induces translocation of α-ENaC toward the apical membrane in situ. Ang II actions on ENaC Po 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. AT1 but not AT2 receptors mediate Ang II actions on ENaC. Unlike its effect in vasculature, Ang II did not increase [Ca2+]i in split-opened distal nephrons as demonstrated using ratiometric Fura-2-based microscopy. However, application of Ang II to mpkCCDc14 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 Po in 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 propose that stimulation of AT1 receptors with subsequent activation of NADPH oxidase signaling pathway mediates Ang II actions on ENaC.

Author List

Mamenko M, Zaika O, Ilatovskaya DV, Staruschenko A, Pochynyuk O

MESH terms used to index this publication - Major topics in bold

Aldosterone
Angiotensin II
Animals
Calcium
Dose-Response Relationship, Drug
Drug Synergism
Enzyme Activation
Epithelial Sodium Channels
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
NADPH Oxidases
Nephrons
Reactive Oxygen Species
Receptor, Angiotensin, Type 1
Renin-Angiotensin System
Sodium