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

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 alpha1 of AMPK inhibits ENaC in epithelial tissues from airways, kidney, and colon and that AMPK regulation of ENaC is absent in AMPKalpha1-/- 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 AMPKalpha1-/- mice. Therefore, AMPKalpha1 is a physiologically important regulator of electrogenic Na(+) absorption and may provide a novel pharmacological target for controlling epithelial Na(+) transport.