Angiotensin II-Stimulated Superoxide Production Is Increased by a Fructose High-Salt Diet and This Contributes to Salt-Sensitive Hypertension

Background: Angiotensin II (Ang-II) increases proximal tubule superoxide (O2-) production significantly more in rats fed a 20% fructose normal-salt diet compared to rats fed a 20% glucose, normal-salt diet. These data suggest that dietary fructose augments the sensitivity of proximal tubule O2- production to Ang-II. A 20% fructose high-salt (3.7% NaCl; FHS) also significantly increases systolic blood pressure (SBP), whereas 20% glucose high-salt (GHS) does not. However, it is unclear whether FHS enhances Ang-II induced oxidative stress in proximal tubules, and whether this contributes to increases in BP in this model. We hypothesized that FHS augments the ability of Ang-II to stimulate superoxide production by proximal tubules, and this contributes to fructose-induced salt-sensitive hypertension. Methods: We measured SBP in male Sprague Dawley rats fed FHS, GHS, FHS plus 3 mM tempol (a O2- scavenger) in the drinking water (FHS+T), and GHS+T for 7 days. Then we measured the effect of 3.7 x 10-8 M Ang-II on O2- production by proximal tubule suspensions from rats fed GHS, FHS, and FHS+T using the lucigenin assay. This concentration was chosen because it was the lowest concentration that significantly stimulated O2- production by proximal tubules from rats fed FHS. Results: FHS increased SBP by 11 ± 2 mmHg, (Day 0: 131 ± 4, Day 7: 142 ± 5 mmHg; n = 5, p < 0.01), while GHS did not (Day 0: 140 ± 3, Day 7: 137 ± 3 mmHg, n = 5). Rats fed FHS+T and GHS+T showed no significant increases in SBP (FHS+T: Δ-1 ± 5, n = 8; GHS+T: Δ-1 ± 4 mmHg, n = 6). Ang-II increased O2- production by 11 ± 1 relative light units (RLU)•μg protein-1•s-1 in proximal tubules from FHS-fed rats (Basal: 53 ± 9, Ang-II: 64 ± 8 RLU•μg protein-1•s-1; n = 11, p < 0.01) but not in proximal tubules from rats fed GHS (Basal: 46 ± 3, Ang-II: 43 ± 5 RLU•μg protein-1•s-1; n = 6). Ang-II did not significantly stimulate O2- production by proximal tubules from rats fed FHS+T (basal: 53 ± 5, Ang-II: 51 ± 4 RLU•μg protein-1•s-1; n = 6). We did not measure Ang-II induced superoxide production in rats fed GHS+T because there was not a significant change in blood pressure. Conclusions: We conclude that a FHS diet enhances the sensitivity of proximal tubule O2- production to Ang-II, and this contributes to fructose-induced salt-sensitive hypertension. Funding: Other NIH Support - NHLBI