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Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice.

ABSTRACT: Essentials Two basic carboxypeptidases are present in plasma, B2 (CPB2) and N (CPN). Cpb2^-/- and Cpn^-/- mice were challenged in a hemolytic uremic syndrome (HUS) model vs. wild type. Cpb2^-/- exacerbates HUS while Cpn^-/- exacerbates cobra venom factor challenge vs. wild type mice. CPB2 and CPN have overlapping but non-redundant roles.

Summary

Background There are two basic carboxypeptidases in plasma. Carboxypeptidase B2 (CPB2) is activated from a circulating zymogen, proCPB2, and carboxypeptidase N (CPN) is constitutively active with both inactivating complement C3a and C5a. Aims To test the roles of CPB2 and CPN in complement-driven mouse models of cobra venom factor (CVF) challenge and hemolytic-uremic syndrome (HUS). Methods Cpb2^-/- , Cpn^-/- and wild-type (WT) mice were compared in an HUS model induced by Shiga toxin and lipopolysaccharide administration and following CVF administration. Results HUS was exacerbated in Cpb2^-/- mice more than in Cpn^-/- mice, compared with WT mice. Cpb2^-/- mice developed the HUS clinical triad of microangiopathic hemolytic anemia, uremia and thrombocytopenia. Treatment with anti-C5 antibody improved survival of both Cpb2^-/- and Cpn^-/- mice. In contrast, when challenged acutely with CVF, the reverse phenotype was observed. Cpn^-/- mice had markedly worse disease than Cpb2^-/- mice, whereas the WT mice were resistant. Conclusions CPN and CPB2 play overlapping but non-redundant roles in regulating complement activation in vivo. The constitutively active CPN is key for inactivation of systemic C5a, whereas CPB2 functions as an on-demand supplementary anaphylatoxin inhibitor in inactivating excessive C5a formed locally.

SUBMITTER: Morser J

PROVIDER: S-EPMC8491566 | biostudies-literature |

REPOSITORIES: biostudies-literature

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