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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.