Responses to Diuretic Treatment in Gene-Targeted Mice Lacking Serum- and Glucocorticoid-Inducible Kinase 1

Background/Aims: Serum- and glucocorticoid-inducible kinase 1 (SGK1) stimulates the epithelial sodium channel (ENaC), renal outer medullary K+ channel 1, Na+/K+-ATPase and presumably the Na+-Cl- cotransporter (NCC). SGK1-deficient mice (sgk(-/-)) show a compensated salt-losing phenotype with secondary hyperaldosteronism. The present experiments explored the role of SGK1 in the response to diuretics. Methods: sgk1(-/-) mice and their wild-type litter-mates (sgk1(+/+)) were treated with the ENaC blocker triamterene (200 mg/l), the Na+-K+-2Cl(-) cotransport inhibitor furosemide (125 mg/l), the NCC blocker hydrochlorothiazide (400 mg/l) and the mineralocorticoid receptor blocker canrenoate (800 mg/l) for 8 days. Renal SGK1 expression was studied using quantitative RT-PCR and immunofluorescence. Results: Diuretic treatment increased SGK1 mRNA and protein expression in the kidney of wild-type sgk1(+/+) mice. The responses to furosemide, hydrochlorothiazide or canrenoate were not different between sgk1(+/+) and sgk1(-/-) mice, and were accompanied by moderate increases in plasma aldosterone and urea concentrations. However, treatment with triamterene in sgk1(-/-) mice (but not in sgk1(+/+) mice) led to severe, eventually lethal, body weight loss as well as increases in plasma aldosterone, urea and K+ concentrations. Conclusions: SGK1 is required for diuretic tolerance to triamterene. The observations confirm the impaired kaliuretic potency of sgk1(-/-) mice and point to a role of SGK1 in renal Na+ reabsorption by mechanisms other than ENaC. Copyright (c) 2009 S. Karger AG, Basel