Targeting Kinin B1R Attenuates Hypertension Through AT1R-Dependent Mechanisms

BACKGROUND: Neurogenic hypertension is chronically high blood pressure that is initiated and maintained through excessive sympathetic nervous system activity and has been associated with increased B1R (kinin B1 receptor) activation. We previously reported a central role for B1R in mediating inflammatory pathways in the development of deoxycorticosterone acetate salt hypertension. Additionally, we identified a causal relationship between B1R expression after Ang II (angiotensin II) stimulation, and that B1R can mediate the bidirectional interaction between neuroinflammation and oxidative stress. However, whether there are any interactions between AT1R (Ang II-type I receptor) and B1R, and if B1R can mediate the effects of Ang II–induced hypertension, has not yet been investigated. METHODS: We used a well-established mouse model of Ang II–induced hypertension to test the hypothesis that B1R activation contributes to increased sympathoexcitation, autonomic dysfunction, oxidative stress, and inflammation, potentially through interactions with AT1R. Wild-type and BIR knockout mice were infused with Ang II or saline via osmotic minipump for 28 days, then functional and molecular changes in response to Ang II were assessed. RESULTS: Ang II in wild-type mice led to significant increases in B1R expression associated with sympathoexcitation, autonomic dysfunction, impaired baroreflex sensitivity, and enhanced blood pressure, whereas these changes were attenuated in B1R gene-deficient mice. B1R was shown to directly interact with AT1R, and activation of B1R was involved with microglial activation and subsequent neuroinflammation, increased neuronal firing, and altered synaptic density. We further used pharmacological blockade of B1R to dismiss potential developmental alterations in gene-deficient mice. Specific B1R antagonist attenuated Ang II–induced increases in blood pressure, supporting the role of B1R in blood pressure regulation. CONCLUSIONS: Our data provide the first evidence of the role of B1R in Ang II–induced hypertension and its interactions with AT1R, highlighting B1R as a potential therapeutic target for hypertension.