Resistance of mice lacking the serum- and glucocorticoid-inducible kinase SGK1 against salt-sensitive hypertension induced by a high-fat diet

Mineralocorticoids enhance expression and insulin stimulates activity of the serum- and glucocorticoid-inducible kinase SGK1, which activates the renal epithelial Na+ channel (ENaC). Under a salt-deficient diet, SGK1 knockout mice (sgk1(-/-)) excrete significantly more NaCl than their wild-type littermates (sgk1(-/-)) and become hypotensive. The present experiments explored whether SGK1 participates in the hypertensive effects of a high-fat diet and high-salt intake. Renal SGK1 protein abundance of sgk1(-/-) mice was significantly elevated after a high-fat diet. Under a control diet, fluid intake, blood pressure, urinary flow rate, and urinary Na+, K+, and Cl+ excretion were similar in sgk1(-/-) and sgk1(-/-) mice. Under a standard diet, high salt (1% NaCl in the drinking water for 25 days) increased fluid intake, urinary flow rate, and urinary Na+, K+, and Cl+ excretion similarly in sgk1(-/-) and sgk1(-/-) mice without significantly altering blood pressure. A high-fat diet alone (17 wk) did not significantly alter fluid intake, urinary flow rate, urinary Na+, K+, or Cl+ excretion, or plasma aldosterone levels but increased plasma insulin, total cholesterol, triglyceride concentrations, and systolic blood pressure to the same extent in both genotypes. Additional salt intake ( 1% NaCl in the drinking water for 25 days) on top of a high-fat diet did not affect hyperinsulinemia or hyperlipidemia but increased fluid intake, urinary flow rate, and urinary NaCl excretion significantly more in sgk1(-/-) than in sgk1(-/-) mice. Furthermore, in animals receiving a high-fat diet, additional salt intake increased blood pressure only in sgk1(-/-) mice ( to 132 +/- 3 mmHg) but not in sgk1(-/-) mice (120 +/- 4 mmHg). Thus lack of SGK1 protects against the hypertensive effects of a combined high-fat/high-salt diet.