Possible involvement of up-regulated salt-dependent glucose transporter-5 (SGLT5) in high-fructose diet-induced hypertension.

Excessive fructose intake causes a variety of adverse conditions (e.g., obesity, hepatic steatosis, insulin resistance and uric acid overproduction). High fructose-induced hypertension is a particularly common and pathologically significant condition induced by excess fructose, but its underlying mechanisms remain unknown. We investigated these mechanisms in 7-week-old male Sprague-Dawley rats fed normal rat food or a diet containing 60% glucose (GLU group) or 60% fructose (FRU group) for 3, 6, or 12 weeks. Daily food consumption was measured to avoid between-group discrepancies in caloric/salt intake, adjusting for feeding amounts. The mean blood pressure of FRU rats was significantly higher (12 weeks GLU: 94.8 ± 3.4 mmHg vs. 12 weeks FRU: 103.7 ± 1.2 mmHg), and fractional sodium excretion was significantly lower (12 weeks GLU: 0.084 ± 0.011% vs. 12 weeks FRU: 0.059 ± 0.08%), indicating that the high-fructose diet caused salt retention. The kidney weight and glomerular surface area were greater in FRU rats (12 weeks GLU: 7495 ± 181 vs. 12 weeks FRU: 9831 ± 164 μm2), suggesting that the high-fructose diet induced an increase in extracellular fluid volume. The expressions of GLUT5 and ketohexokinase, an enzyme required for fructose metabolism, were up-regulated in the FRU group rats (GLUT5 12 weeks GLU: 104.7 ± 15.4% vs. 12 weeks FLU: 309.0 ± 99.9%, ketohexokinase 12 weeks GLU: 129.6 ± 3.5% vs. 12 weeks FLU: 163.9 ± 13.0%). Cortical ATP levels were significantly lower in FRU rats (12 weeks GLU: 9.82 ± 1.26 nmol/mg protein vs. 12 weeks FRU: 7.59 ± 1.68 nmol/mg protein), possibly indicating ATP consumption due to fructose metabolism. Unlike in previous reports the high-fructose diet did not affect NHE3 expression (12 weeks GLU: 166.1 ± 6.3% vs. 12 weeks FLU: 142.0 ± 5.9%). A gene chip analysis conducted to identify susceptible molecules revealed that only Slc5a10 (corresponding to SGLT5) showed >two-fold up-regulation in FRU versus GLU rats. RT-PCR and in situ hybridization confirmed the SGLT5 up-regulation (12 weeks GLU: 75.0 ± 5.8% vs. 12 weeks FLU: 230.1 ± 16.0%). Our findings may indicate that the high-fructose diet increased sodium reabsorption principally through up-regulated SGLT5, finally causing salt-sensitive hypertension.