Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome

Abstract

Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 μg/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 ( sgk1−/−) and their wild-type littermates ( sgk1+/+). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1+/+and 15/44 of sgk1−/−mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1+/+mice. Urinary sodium excretion reached signficantly lower values in sgk1+/+mice (15 ± 5 μmol/mg crea) than in sgk1−/−mice (35 ± 5 μmol/mg crea) and was associated with a significantly higher body weight gain in sgk1+/+compared with sgk1−/−mice (+6.6 ± 0.7 vs. +4.1 ± 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1−/−mice than in sgk1+/+mice leading to uremia and a reduced median survival in sgk1−/−mice (29 vs. 40 days in sgk1+/+mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.