JS ISH-ISN-1 OXIDATIVE STRESS, THE KIDNEY AND HYPERTENSION CLINICAL IMPLICATIONS.

OBJECTIVE: CKD progression is accelerated by hypertension and impaired myogenic responses (MRs) of renal afferent arterioles leading to renal barotrauma. We tested the hypothesis that reactive oxygen species (ROS) underlie both these processes and that ROS metabolism by tempol would thereby protect kidneys.

DESIGN AND METHODS: Rat and mouse 5/6 nephrectomy models of reduced renal mass (RRM) vs sham were fed high salt for 3 months during BP telemetry. Individual afferent arterioles were isolated and perfused. ROS were assessed by excretion of 8-isoprostane F2α (8-Iso) and H2O2 and by fluorescence microscopy of afferent arterioles.

RESULTS: Rats and mice with RRM had a > 4-fold increase in excretion of 8-Iso, H2O2, and albumin and hypertension that were prevented in those given 2% tempol in drinking water. Their afferent arteriolar contractions with increases in perfusion pressure (PP) from 40 to 80 mmHg (MRs) were severely impaired (Δ diameter -2 +/- 4 vs - 19 +/- 4%; P < 001), accompanied by increased arteriolar O2 (23 +/- 4 vs 12 +/- 2%; P < 0.01) and H2O2 (32 +/- 4 vs 5 +/- 2%; P < 0.005). Metabolism of O2 with SOD worsened MRs, yet metabolism of H2O2 with catalase preserved normalized MRs in mice with RRM (-22 +/- 3%; ns vs sham). RRM mice drinking 2% tempol throughout had normal excretion and arteriolar H2O2 and normal MRs (-20 +/- 3%; ns vs sham).

CONCLUSIONS: Increased ROS in rodent CKD models underlies salt sensitivity whereas increased H2O2 specifically underlies impaired MRs. Tempol corrects both O2 and H2O2 thereby preserves MRs and prevents hypertension and renal damage. Thus, antioxidant therapy with drugs such as tempol may provide a novel approach to renal protection.