Kininase I drives angiotensin II-induced hypertension through activation of the bradykinin B1 receptor.

Abstract

Background and purpose: Kininase I, comprising carboxypeptidase N (CPN) and carboxypeptidase M, regulates kinin activity and is up-regulated during injury, inflammation and immune activation. Under these conditions, kininase I converts bradykinin and kallidin into des-Arg kinins, primary endogenous agonists of the bradykinin B₁ receptor (R). B₁R signalling promotes vasoconstriction and inflammatory responses in the pathogenesis of hypertension. The roles of kininase I in regulating kinin-dependent signalling and inter-system interactions that contribute to blood pressure control and hypertensive organ injury remain poorly defined.

Experimental approach: CPN knockout (CPNKO) and wild-type (WT) mice underwent chronic Ang II infusion to evaluate the role of CPN, and a separate cohort of WT mice were treated with the kininase I inhibitor Mergetpa alongside angiotensin (Ang) II to assess the effects of kininase I inhibition.

Key results: Ang II in WT mice increased blood pressure and was accompanied by sympathetic overactivation, increased B₁R expression, cardiac remodelling, immune cell infiltration and complement activation. CPNKO mice exhibited attenuated Ang II-induced hypertension, reduced B₁ receptor expression, decreased cardiac fibrosis and blunted sympathetic activation. Pharmacologic inhibition of kininase I with Mergetpa reduced Ang II-induced increases in blood pressure, limited B₁R up-regulation and suppressed complement activation and immune cell infiltration.

Conclusions and implications: These findings identify kininase I as a critical enzymatic regulator linking the renin angiotensin and kallikrein kinin systems and highlight a mechanism through which cardiovascular and immune signalling pathways interact to drive hypertension. These results position kininase I as a potential therapeutic target for the treatment of hypertension.