AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated

Joana Almaça, Patthara Kongsuphol, Bernhard Hieke, Jiraporn Ousingsawat, Benoit Viollet, Rainer Schreiber, Margarida D. Amaral, Karl Kunzelmann

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

The metabolic sensor adenosine-monophosphate-activated kinase (AMPK) detects the cellular energy status and adjusts metabolic activity according to the cytosolic AMP to ATP ratio. Na+ absorption by epithelial Na + channels (ENaC) is a highly energy-consuming process that is inhibited by AMPK. We show that the catalytic subunit α1 of AMPK inhibits ENaC in epithelial tissues from airways, kidney, and colon and that AMPK regulation of ENaC is absent in AMPKα1-/- mice. These mice demonstrate enhanced electrogenic Na+ absorption that leads to subtle changes in intestinal and renal function and may also affect Na+ absorption and mucociliary clearance in the airways. We demonstrate that AMPK uses the ubiquitin ligase Nedd4-2 to inhibit ENaC by increasing ubiquitination and endocytosis of ENaC. Thus, enhanced expression of epithelial Na+ channels was detected in colon, airways, and kidney of AMPKα1-/- mice. Therefore, AMPKα1 is a physiologically important regulator of electrogenic Na+ absorption and may provide a novel pharmacological target for controlling epithelial Na+ transport.

Original languageEnglish (US)
Pages (from-to)713-721
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume458
Issue number4
DOIs
StatePublished - Aug 2009
Externally publishedYes

Keywords

  • AMPK
  • AMPKα1
  • ENaC
  • Epithelial Na+ channel
  • Knockout

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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