Knockdown of Bradykinin B1 Receptor Reduces Neuro‐inflammation and Prevents the Development of Salt‐Sensitive Hypertension

We previously reported that DOCA‐salt hypertension is associated with increased bradykinin B1 receptor (B1R) expression in the brain. In the present study, we tested the hypothesis that B1R knockdown prevents the development of hypertension. To test this hypothesis, wild‐type (WT) and B1R knockout (KO) mice were implanted with telemetry probes for conscious blood pressure (BP) monitoring. DOCA (1 mg/g, sc) was implanted following baseline BP recording and drinking water was replaced by 1% NaCl solution. Autonomic function was analyzed using a pharmacological method involving ip injection of propranolol (4 mg/kg) and atropine (1 mg/kg). Changes in heart rate (ΔHR) were used as index of sympathetic and parasympathetic tones. Baseline mean arterial pressure (MAP) was not different between WT and B1R KO mice (102±2 vs. 104±5 mmHg), nor were ΔHR following assessment of sympathetic (−73±6 vs. −75±15 beats/minute) or parasympathetic tone (+166±7 vs. +153±12 beats/minute). Three weeks after DOCA‐salt treatment, MAP was significantly increased in WT mice (138±3 mmHg, P <0.01 vs. baseline). However, this increase was blunted in B1R KO mice (121±2 mmHg, P <0.05 vs. WT+DOCA). In addition, DOCA‐salt mediated enhancement of cardiac sympathetic drive (increased bradycardia to propranolol, −145±21 beats/minutes, P <0.01 vs. baseline) and reduction of parasympathetic tone (reduced tachycardia to atropine, +111±8 beats/minute, P <0.01 vs. baseline) were normalized in B1R KO mice (−72±13 and +165±6 beats/minute, respectively, P <0.05 vs. WT+DOCA). DOCA‐salt treatment resulted in sympathoexcitation in WT mice, as indicated by increased urinary norepinephrine levels (299±23 ng/ml, P <0.05 vs. control), but this increase was blunted in B1R KO mice with DOCA (172±30 ng/ml, P <0.05 vs. WT+DOCA). Moreover, pro‐inflammatory high‐mobility group box 1 (HMGB1) and cyclooxygenase 2 protein levels were significantly upregulated in the hypothalamus following DOCA treatment in WT mice (2.5 and 2 fold, respectively, P <0.05 vs. control) but not in B1R KO mice. WT mice treated with DOCA‐salt showed increased inflammation as indicated by increased gene expression of TNF (3 fold, n=9, p<0.001 vs. WT), IL‐1beta (8 fold, n=9, p<0.001 vs. WT) and IL‐6 (5 fold, n=9, p<0.01 vs. WT) in the hypothalamic paraventricular nucleus (PVN) which was attenuated in B1R KO mice. Taken together, these data suggest that B1R knockdown prevents the development of hypertension, possibly through decreased sympathetic activity, reducing HMGB1 expression, and diminishing its downstream neuroinflammatory cascade. Support or Funding Information 15SDG25720021 (SS), NIH/NHLBI (HL093178) (EL), and P30GM106392