Elevated fructose intake induces hypertension in dahl salt sensitive (SS) rats on a normal na diet: Role of SPAK (STK39) and NKCC2

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Increased fructose consumption in sweetened beverages is associated to increased cardiovascular events and hypertension in patients. We found that in normal, salt resistant, Sprague Dawley (SD) rats, a moderately high fructose intake (20% fructose drinking water) induced salt sensitive hypertension whereas fructose in normal Na diet had little effect. The mechanisms by which fructose intake induced salt sensitive hypertension are unclear. Fructose directly increases the activity of the Na-K-2Cl cotransporter NKCC2 in the thick ascending limb (TAL), and when consumed for 7 days or more, increases phosphorylation of NKCC2, suggesting that this may contribute to fructose induced salt sensitive hypertension. The kinases upstream of NKCC2 phosphorylation, SPAK and OSR1 were also activated by fructose intake. The Dahl SS rat has higher NKCC2 and SPAK phosphorylation in the TAL. We hypothesized that elevated fructose intake causes hypertension in Dahl SS rats on normal Na, but not in SD rats, and that SPAK and NKCC2 phosphorylation are involved. We measured systolic BP (SBP) by radiotelemetry in conscious SD rats fed normal Na (0.4% Na) and 20% fructose in drinking water. SBP minimally increased by 7±2 mmHg (from 122±3 to 129±3 mmHg, p<0.05) after 4 weeks of high fructose and normal Na. In Dahl SS rats fed normal Na, SBP increased by 25±4 mmHg (from 148±3 to 173±4 mmHg, p<0.05 vs SD rat) after 4 weeks of high fructose intake. To study SPAK, we generated Dahl SS rats with genetic deletion of SPAK (SPAK KO). Baseline SBP was lower in SPAK KO (133±2 mmHg, p<0.05), and minimally increased by 10±3 mmHg (from 133±2 to 144±3 mmHg, p<0.05 vs Dahl SS) after 4 weeks of high fructose intake. The decreased effect of fructose in SPAK KO rats may be related to lower NKCC2 phosphorylation because phosphoNKCC2/total NKCC2 was 33 ± 7% lower (p<0.05) in TALs from SPAK KO compared to Dahl SS on high fructose for 14 days. We concluded that a moderately elevated fructose intake induces hypertension in Dahl SS rats on normal Na diet, but not in SD rats. Fructose-induced hypertension in Dahl SS is in part mediated by SPAK and related to higher NKCC2 phosphorylation. Our data suggest that in patients with genetic susceptibility to high salt, BP may also be enhanced by high fructose consumption.



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