SGK1 is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase stimulates the renal epithelial Na+ channel ENaC and may thus participate in blood pressure regulation. Hyperinsulinemia is triggered by dietary fructose, which sensitizes blood pressure to salt intake. To explore the role of SGK1 under these conditions, experiments were performed in gene targeted mice lacking functional SGK1 (sgk1-/- ) and their wild type littermates (sgk1+/+). Renal SGK1 transcript levels of sgk1+/+mice were significantly elevated after fructose diet. Under control diet fluid intake, urinary flow rate, urinary Na+ , K+ , and Cl- excretion as well as blood pressure were similar in sgk1-/- and sgk1+/+mice. High fructose diet increased fluid intake and urinary flow rate in both genotypes but did not significantly alter urinary Na+ , K+ , or Cl- excretion in either genotype. Additional high NaCl diet (4% NaCl) did not significantly alter fluid intake and urine volume but significantly increased urinary output of Na+ and Cl- to values significantly higher in sgk1-/- than in sgk1+/+mice. Blood pressure was similar in sgk1+/+ and sgk1-/- mice at control diet or fructose alone but increased only in sgk1 +/+mice following combined fructose and high-salt intake. The observations reveal a pivotal role of SGK1 in the development of hypertension following coincidence of hyperinsulinemia and salt excess.