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) 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 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.