Blunted hypertensive effect of combined fructose and high-salt diet in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1

Departments of 1 Pharmacology and Toxicology, 2 Physiology, and 3 Anatomy, University of Tübingen, Tübingen; 4 Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg; 5 Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany; and 6 Departments of Medicine and Pharmacology, University of California San Diego and Veterans Affairs San Diego Health Care System, San Diego, California Submitted 31 May 2005 ; accepted in final form 8 November 2005 Serum- and glucocorticoid-inducible kinase (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase stimulates the renal epithelial Na + channel and may thus participate in blood pressure regulation. Hyperinsulinemia is triggered by dietary fructose, which sensitizes blood pressure for salt intake. The role of SGK1 in hypertensive effects of combined fructose and high-salt intake was thus explored in SGK1 knockout mice ( 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, and blood pressure were similar in sgk1 –/– and sgk1 +/+ mice. Addition of 10% fructose to drinking water increased fluid intake and urinary flow rate in both genotypes, and did not significantly alter urinary Na + , K + , and Cl – output in either genotype. Additional high NaCl diet (4% NaCl) did not significantly alter fluid intake and urine volume but markedly increased urinary output of Na + and Cl – , approaching values significantly ( P < 0.05) larger in sgk1 –/– than in sgk1 +/+ mice (Na + : 2,572 ± 462 vs. 1,428 ± 236; Cl – : 2,364 ± 388 vs. 1,379 ± 225 µmol/24 h). Blood pressure was similar in sgk1 +/+ and sgk1 –/– mice at control diet or fructose alone but increased only in sgk1 +/+ mice (115 ± 1 vs. 103 ± 0.7 mmHg, P < 0.05) after combined fructose and high-salt intake. Acute intravenous insulin infusion (during glucose clamp) caused antinatriuresis in sgk1 +/+ mice, an effect significantly blunted in sgk1 –/– mice. The observations reveal a pivotal role of SGK1 in insulin-mediated sodium retention and the salt-sensitizing hypertensive effect of high fructose intake. insulin; blood pressure; salt sensitivity; epithelial sodium channel; kidney Address for reprint requests and other correspondence: F. Lang, Dept. of Physiology, Univ. of Tübingen, Gmelins