British journal of pharmacology · 2026
Kininase I drives angiotensin II-induced hypertension through activation of the bradykinin B1 receptor.
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White Acacia, Theobald Drew, Johnston Alexandra, Tulis David A, Hannan Johanna, Sriramula Srinivas
Аннотация
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.
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.