Transactivation Of Brain ADAM17 In Angiotensin II-Induced Hypertension Can Be Prevented By Kinin B1 Receptor Blockade

A disintegrin and metalloprotease 17 (ADAM17) has been implicated in mediating inflammation in several cardiovascular diseases. Targeting brain ADAM17 using siRNA revealed a reduction in blood pressure, confirming its role in hypertension. Previously, we reported that kinin B1 receptor (B1R) activation increases ADAM17 activity in primary hypothalamic neurons, while pretreatment with a B1R antagonist mitigated this effect. However, whether there is a direct interaction between ADAM17 and B1R in hypertension is unknown. In this study, we tested the hypothesis that B1R blockade will prevent the transactivation of ADAM17, thereby, preventing the development of angiotensin II-induced hypertension. Male and female C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) were administered Ang II (600 ng/kg/min; SC, 2 weeks) or saline via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Both male and female B1RKO mice showed similar attenuation of Ang II-induced hypertension. Ang II-infusion led to a significant upregulation of ADAM17 in the PVN of WT mice and was blunted in B1RKO mice (p<0.05, n=3). Proximity ligation assay (PLA) was used to examine close proximity (<40nm) interactions between two receptors. ADAM17-B1R interactions in the PVN of hypertensive mice were significantly increased (p<0.05, n=3). To further understand this correlation, primary neurons and microglia from the hypothalamus of neonatal WT mice were cultured and treated with Ang II (300 nM) for 24 hours. Ang II increased B1R and ADAM17 protein expression in both cell types and was prevented by a B1R antagonist SSR240612 (10 uM) (p<0.05, n=5). To supplement these findings, PLA was used on primary neurons and microglia and revealed an increase in ADAM17-B1R interactions following Ang II. Furthermore, B1R antagonism attenuated this ADAM17-B1R interaction in both neurons and microglia (p<0.05, n=5). Our data provides novel evidence that B1R blockade can attenuate Ang II-induced hypertension in the brain, possibly through a reduction in B1R-ADAM17 interactions, suggesting that B1R blockade may serve as a potential antihypertensive therapeutic agent.