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1 Department of Pharmacology & Toxicology, University of Tubingen, Tubingen, Germany
2 Department of Physiology, University of Tubingen, Tubingen, Germany
3 Department of Anatomy, University of Tubingen, Tubingen, Germany
4 Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Heidelberg, Germany
5 Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany
6 Departments of Medicine & Pharmacology, University of California San Diego & VASDHCS, San Diego, California, USA
* To whom correspondence should be addressed. E-mail: florian.lang{at}uni-tuebingen.de.
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. Hyperinsulinism 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 following 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 neither 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+: 2572±462 vs. 1428±236; Cl-: 2364±388 vs. 1379±225 µmol/24h). 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) following 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.
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