Salt-inducible
kinase 1 (SIK1) in epithelial cells mediates the increases in active
sodium transport (Na(+), K(+)-
ATPase-mediated) in response to elevations in the intracellular concentration of
sodium. In lung alveolar epithelial cells increases in active
sodium transport in response to β-
adrenergic stimulation increases
pulmonary edema clearance. Therefore, we sought to determine whether SIK1 is present in lung epithelial cells and to examine whether
isoproterenol-dependent stimulation of Na(+), K(+)-
ATPase is mediated via SIK1 activity. All three SIK
isoforms were present in airway epithelial cells, and in alveolar epithelial cells type 1 and type 2 from rat and mouse lungs, as well as from human and mouse cell lines representative of lung alveolar epithelium. In mouse lung epithelial cells, SIK1 associated with the Na(+), K(+)-
ATPase α-subunit, and
isoproterenol increased SIK1 activity.
Isoproterenol increased Na(+), K(+)-
ATPase activity and the incorporation of Na(+), K(+)-
ATPase molecules at the plasma membrane. Furthermore, those effects were abolished in cells depleted of SIK1 using
shRNA, or in cells overexpressing a SIK1
kinase-deficient mutant. These results provide evidence that SIK1 is present in lung epithelial cells and that its function is relevant for the action of
isoproterenol during regulation of active
sodium transport. As such, SIK1 may constitute an important target for
drug discovery aimed at improving the clearance of
pulmonary edema.