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

Lama Al-Qusairi, Denis Basquin, Matteo Stifanelli, Paul A. Welling, Olivier Staub

Research output: Contribution to journalArticlepeer-review


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 Sgk1Pax8/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, Sgk1Pax8/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 Sgk1Pax8/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.

Original languageEnglish (US)
Article numbere15188
JournalPhysiological Reports
Issue number4
StatePublished - Feb 2022

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology


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