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 (s gk– /– ) 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 littermates (s gk1+ /+ ) 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 s gk1+ /+ 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