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

ABSTRACT: 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.

SUBMITTER: Al-Qusairi L 

PROVIDER: S-EPMC8883148 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature