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GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS
Departments of 1Pharmacology and Toxicology, 2Physiology, and 3Anatomy, University of Tübingen, Tübingen; 4Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg; 5Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany; and 6Departments 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
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