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

BACKGROUND: A fructose high-salt (FHS) diet increases systolic blood pressure and Ang II (angiotensin II)–stimulated proximal tubule (PT) superoxide (O 2 − ) production. These increases are prevented by scavenging O 2 − 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) O 2 − 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), 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 2 − 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 O 2 − 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 2 − with tempol. CONCLUSIONS: SGLT5-mediated PT fructose reabsorption is required for FHS to augment Ang II–stimulated proximal nephron O 2 − production, and increases in PT oxidative stress likely contribute to FHS-induced hypertension.