Glut5 Knockdown in the Nucleus Tractus Solitarii Alleviates Fructose-Induced Hypertension in Rats.

BACKGROUND: Several studies have suggested mechanisms whereby excessive fructose intake increases blood pressure (BP). Glucose transporter 5 (GLUT5) is a fructose transporter expressed on enterocytes, and its involvement in the nucleus tractus solitarius (NTS)-modulated increase in BP following fructose intake remains unclear. OBJECTIVE: Herein, we investigated whether NTS Glut5 knockdown can alleviate fructose-induced hypertension in rat models. METHODS: Male Wistar-Kyoto rats (6-8 weeks old, average weight: 230 g) randomly assigned into four groups (Con, Fru, Fru + S, and Fru + KD). The Con group rats had ad libitum access to regular water, and the other three groups were provided 10% fructose water ad libitum for 4 weeks (2 weeks before lentiviral transfection in the Fru + S and Fru + KD groups). Glut5 short hairpin RNA (shRNA) was delivered into the NTS of rats using a lentivirus system. Fructose-induced hypertension was assessed via the tail-cuff technique, a non-invasive blood pressure measurement approach. GLUT5-associated and other insulin signaling pathways in the NTS of rats were assessed using immunofluorescence and immunoblotting analyses. We evaluated between-group differences using the Mann-Whitney U test or Kruskal-Wallis one-way analysis of variance. RESULTS: Compared with the Fru + S group, the Fru + KD group had reduced sympathetic nerve hyperactivity (48.8 ± 3.2 bursts/min, P < 0.05), improved central insulin signaling, upregulated protein kinase B (AKT, 3.0-fold) and neuronal nitric oxide synthase (nNOS, 2.78-fold) expression, and lowered BP (17 ± 1 mmHg, P < 0.05). Moreover, Glut5 knockdown restored AMPK-dependent signaling and reduced fructose-induced oxidative stress 2.0-fold, thus decreased NADPH oxidase in p67-phox 1.9-fold within the NTS. CONCLUSIONS: Fructose induced reactive oxygen species generation in the NTS of rats through GLUT5 and receptor for advanced glycation end products (RAGE) signaling, thus impairing the AKT-nNOS-NO signaling pathway and ultimately causing hypertension.