Interactions between carboxypeptidase M and kinin B1 receptor in endothelial cells.

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2019 Oct

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Carboxypeptidase M (CPM) is a glycosylphosphatidylinositol anchored enzyme that plays an important role in the kallikrein-kinin system (KKS). CPM catalytic domain hydrolyzes Arg from C-terminal peptides (i.e., bradykinin and kallidin), generating des-Arg-kinins, the agonists of B1 receptor (B1R). It is known that CPM and kinin B1R are co-localized in the plasma membrane microdomains, where they interact with each other, facilitating receptor signaling. We hypothesized here that this CPM-B1R interaction could also affect the activity of the enzyme. Thus, in this work, we evaluated the impact of B1R presence or absence on CPM activity and expression, using primary culture of microvascular endothelial cells from wild-type, kinin B1R knockout mice (B 1 -/- ), and transgenic rats overexpressing B1 receptor exclusively in the endothelium. In addition, HEK293T cells, as wells as B 1 -/- primary culture of endothelial cells, both transfected with B1R, were also used. CPM expression and activity were downregulated in cells of knockout mice compared to control and this reduction was rescued after B1R transfection. Cells overexpressing B1R presented higher levels of CPM mRNA, protein, and activity. This profile was reverted by pre-incubation with the B1R antagonist, R715, in highly expressing receptor cells. Our data show that kinin B1R positively modulates both CPM expression and activity, suggesting that CPM-B1R interaction in membrane microdomains might affect enzyme activity, beyond interfering in receptors signaling. This work highlights the interactions among different components of KKS and contributes to a better understanding of its patho-physiological role.

Citation

Paola Bianchi Guimarães, Rafael Filippelli da Silva, Carolina Caldas Hoff, Liliam Fernandes, Clovis Ryuichi Nakaie, Jair Ribeiro Chagas, Adriana Karaoglanovic Carmona, Michael Bader, João Bosco Pesquero. Interactions between carboxypeptidase M and kinin B1 receptor in endothelial cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2019 Oct;68(10):845-855