Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB133

Poster Communications

High chloride silences the aldosterone - mineralocorticoid receptor - epithelial Na+-channel - pathway in the distal nephron

H. Vitzthum1, C. Meyer-Schwesinger1, H. Ehmke1

1. Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.


As a long appreciated but still unresolved phenomenon, dietary potassium (K+) supplementation in the setting of high salt (NaCl) intake exerts a natriuretic effect, even though it simultaneously increases plasma aldosterone levels. Generally, aldosterone strongly enhances renal sodium (Na+) retention by binding to the mineralocorticoid receptor (MR) in the distal nephron, which increases the activity of the amiloride-sensitive epithelial Na+-channel ENaC. Even though recent studies suggest that deactivation of the thiazide-sensitive NaCl cotransporter (NCC) contributes to the natriuretic effect of high potassium intake, it remains unexplained why this effect is not counterbalanced by an amplified Na+ reabsorption via the activated aldosterone-MR-ENaC pathway. We therefore questioned whether a further mechanism exists, which in the context of high salt and high potassium intake impedes the aldosterone-MR-ENaC pathway to prevent Na+ reabsorption in the aldosterone-sensitive distal nephron. We analyzed the effect of normal or high potassium diet on MR localization, ENaC mRNA and protein expression, and ENaC activity in salt replete mice. The effects of high extracellular chloride concentration [Cl-] on MR localization and ENaC expression in mCCD cells were also determined. We found that MR translocation to the nucleus, activation of ENaC, and ENaC-dependent Na+ reabsorption were undetectable in Na+-replete mice receiving a high KCl diet in spite of high plasma aldosterone concentrations. Increasing extracellular [Cl-] also suppressed aldosterone-induced MR translocation and ENaC mRNA and protein expression in mCCD cells in vitro. The aldosterone response was rescued at the biochemical as well as functional level in vivo when the increase in extracellular [Cl-] was prevented during the high potassium diet. These findings show that aldosterone signaling in the kidney is silenced by increased extracellular [Cl-] and provide an explanation for the natriuretic effect of potassium in the presence of a high NaCl consumption, characteristic for the Western diet.

Where applicable, experiments conform with Society ethical requirements