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Knocking Out Sodium Glucose-Linked Transporter 5 Prevents Fructose-Induced Renal Oxidative Stress and Salt-Sensitive Hypertension.

Hypertension 2024 March 29
BACKGROUND: A fructose high-salt (FHS) diet increases systolic blood pressure and Ang II (angiotensin II)-stimulated proximal tubule (PT) superoxide (O2 - ) production. These increases are prevented by scavenging O2 - or an Ang II type 1 receptor antagonist. SGLT4 (sodium glucose-linked cotransporters 4) and SGLT5 are implicated in PT fructose reabsorption, but their roles in fructose-induced hypertension are unclear. We hypothesized that PT fructose reabsorption by SGLT5 initiates a genetic program enhancing Ang II-stimulated oxidative stress in males and females, thereby causing fructose-induced salt-sensitive hypertension.

METHODS: We measured systolic blood pressure in male and female Sprague-Dawley (wild type [WT]), SGLT4 knockout (-/- ), and SGLT5-/- rats. Then, we measured basal and Ang II-stimulated (37 nmol/L) O2 - production by PTs and conducted gene coexpression network analysis.

RESULTS: In male WT and female WT rats, FHS increased systolic blood pressure by 15±3 (n=7; P <0.0027) and 17±4 mm Hg (n=9; P <0.0037) mm Hg, respectively. Male and female SGLT4-/- had similar increases. Systolic blood pressure was unchanged by FHS in male and female SGLT5-/- . In male WT and female WT fed FHS, Ang II stimulated O2 - production by 14±5 (n=6; P <0.0493) and 8±3 relative light units/µg protein/s (n=7; P <0.0218), respectively. The responses of SGTL4-/- were similar. Ang II did not stimulate O2 - production in tubules from SGLT5-/- . Five gene coexpression modules were correlated with FHS. These correlations were completely blunted in SGLT5-/- and partially blunted by chronically scavenging O2 - with tempol.

CONCLUSIONS: SGLT5-mediated PT fructose reabsorption is required for FHS to augment Ang II-stimulated proximal nephron O2 - production, and increases in PT oxidative stress likely contribute to FHS-induced hypertension.

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