Does the early aldosterone‐induced SGK1 play a role in early Kaliuresis?

Urinary K(+) potassium excretion rapidly increases after a potassium‐rich meal. The early aldosterone‐induced sgk1 gene (encoding serum and glucocorticoid‐induced kinase 1), activates potassium clearance, but the role of this kinase in the early activation of K(+) secretion has not been clearly defined. Here, we challenged inducible renal‐tubule‐specific Sgk1(Pax8) (/) (LC1) knockout mice with an acute high‐potassium load (HK:5%K(+)) and compared the physiological and molecular responses to control mice. We observe that urinary excretion after a K(+) load over the first 3 h is not dependent on SGK1 but is coincident with the rapid dephosphorylation of the Na(+),Cl(−)‐cotransporter (NCC) to increase distal salt delivery. Molecular analyses indicate that whereas SGK1‐mediated phosphorylation of the ubiquitin‐protein ligase NEDD4‐2 begins to increase by 3h, SGK1‐dependent proteolytic activation of ENaC only becomes detectable after 6 h of HK intake. Consistent with SGK1‐dependent ENaC activation via inhibition of NEDD4‐2‐mediated ubiquitylation, Sgk1(Pax8) (/) (LC1) mice are unable to efficiently inhibit NEDD4‐2 or increase ENaC cleavage after 6 h of HK. Nevertheless, no defect in acute K(+) balance was detected in the mutant mice after 6 h of HK. Moreover, we found that Sgk1(Pax8) (/) (LC1) mice reduce NCC phosphorylation and NCC‐mediated salt absorption to a greater extent than control mice after a K(+) load, promoting increased amiloride‐sensitive Na(+)‐reabsorption via ENaC to maintain adequate kaliuresis. Together, these data indicate that: (a) during the early 3 h of HK intake, K(+) excretion is SGK1‐independent even under an extreme K(+) challenge, (b) shortly after, SGK1 inhibits NEDD4‐2 and activates ENaC to stimulate K(+)‐secretion, (c) SGK1‐dependent phosphorylation of NCC occurs, acting more likely as a brake pedal to prevent excessive K(+) loss.