Kinin B1 Receptor Knockdown Prevents DOCA‐Salt Hypertension by Modulating Mitochondrial Oxidative Stress in the Brain

The imbalance between reactive oxygen species (ROS) production and anti‐oxidant capacity in the central nervous system results in oxidative stress and is implicated in the pathogenesis of hypertension. Deoxycorticosterone acetate (DOCA)‐salt hypertension is associated with increased expression of the pro‐inflammatory kinin B1 receptor (B1R) in the brain. We previously reported that DOCA‐salt hypertension is attenuated in global B1R knockout (B1RKO) mice. However, the functional role of B1R in inducing oxidative stress within the brain during neurogenic hypertension has not been fully studied. In this study, we tested the hypothesis that the beneficial effects of B1R knockdown are mediated by reduction in mitochondrial oxidative stress in the brain. DOCA‐salt treatment (1mg/g body wt. DOCA, 1% saline in drinking water for 3 weeks) resulted in significantly lower blood pressure (BP; telemetry) level in B1RKO mice (121 ±2 mmHg, n=12) compared to wild‐type controls (WT) (138 ±3 mmHg, n=12). DOCA‐salt treatment resulted in decreased catalase (79.1 ±5.6 vs. 150.3 ±10.4 mmol/min/ml, p<0.01), total superoxide dismutase (SOD, 4.19 ±0.3 vs. 5.97 ±0.3 U/ml, p<0.01), and the mitochondrial antioxidant manganese SOD (0.67 ±0.09 vs. 1.58 ±0.05 U/ml, p<0.01) activities in hypothalamic homogenates of WT mice, which were prevented in B1RKO mice (134.8 ±4.6 mmol/min/ml, 5.89 ±0.1 U/ml, and 1.68 ±0.22 U/ml, respectively, p<0.01). WT mice treated with DOCA‐salt showed increased oxidative stress as indicated by increased total ROS levels in the hypothalamus as measured using electron paramagnetic resonance spectrometer. This increase in ROS production was not observed in B1RKO mice treated with DOCA‐salt. Furthermore, DOCA‐salt hypertension resulted in decreased phosphorylation of eNOS‐ser1177 in the PVN (35 ±5 % decrease, n=9, p<0.05 vs WT), which was prevented in B1RKO mice. In addition, the gene expression of PPAR Gamma coactivator (PGC) 1‐Alpha and Uncoupling protein‐2 (UCP‐2), two important genes involved in mitochondrial function, were decreased in the PVN of DOCA‐salt treated WT mice but not in B1RKO mice. Together, these data provide evidence that kinin B1R knockdown reduces mitochondrial oxidative stress, improves antioxidant and nitric oxide signaling, and there by attenuates the development of DOCA‐salt hypertension. Support or Funding Information The American Heart Association (15SDG25720021) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .