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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 81; no. 6; pp. 1296 - 1307
• Main Authors: Forester, Beau R, Zhang, Ronghao, Schuhler, Brett, Brostek, Autumn, Gonzalez-Vicente, Agustin, Garvin, Jeffrey L
• Format: Journal Article
• Language: English
• Published: United States 01.06.2024
• Subjects: Angiotensin II; Animals; Blood Pressure - drug effects; Blood Pressure - physiology; Disease Models, Animal; Female; Fructose - pharmacology; Hypertension - chemically induced; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Male; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary - adverse effects; Sodium-Glucose Transport Proteins - genetics; Sodium-Glucose Transport Proteins - metabolism; sodium; fructose; glucose; superoxides; angiotensin II
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.123.22535

A fructose high-salt (FHS) diet increases systolic blood pressure and Ang II (angiotensin II)-stimulated proximal tubule (PT) superoxide (O ) production. These increases are prevented by scavenging O 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. 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) O production by PTs and conducted gene coexpression network analysis. In male WT and female WT rats, FHS increased systolic blood pressure by 15±3 (n=7; <0.0027) and 17±4 mm Hg (n=9; <0.0037), 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 O production by 14±5 (n=6; <0.0493) and 8±3 relative light units/µg protein/s (n=7; <0.0218), respectively. The responses of SGTL4 were similar. Ang II did not stimulate O 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 O with tempol. SGLT5-mediated PT fructose reabsorption is required for FHS to augment Ang II-stimulated proximal nephron O production, and increases in PT oxidative stress likely contribute to FHS-induced hypertension.