gms | German Medical Science

Natriuretic peptides (NP) like atrial (ANP) and B-type (BNP) natriuretic peptide are cyclic peptide hormones mainly of cardiac origin with natriuretic and vasodilator effects. NP are quickly cleared from circulation by (a) binding to a clearance receptor with the subsequent internalization and cleavage by cytoplasmic enzymes and (b) degradation by extracellular peptidases. The neutral endopeptidase (NEP), a membrane bound type-II metallopeptidase of the M13 family, is generally regarded to be the main enzyme for NP-degradation. However, our own studies with membranes of wildtype and NEP-knockout mice showed BNP resistance for NEP degradation and thus BNP-degrading activity independent from NEP.

In this study we investigated which peptidase is responsible for the mouse BNP degradation in murine kidney using class-specific inhibitors. The BNP-degrading activity was completely inhibited by the metalloprotease inhibitor EDTA, but not by phosphoramidon, which inhibits e.g. NEP, NEP2 and endothelin-converting enzyme. Further investigations with specific metalloendoproteinase inhibitors enabled us to identify meprin A (EC 3.4.24.18) as a promising candidate degrading BNP. Meprin A is a phosphoramidon- insensitive multimeric metalloprotease expressed in the brush borders of kidney proximal tubules that hydrolyzes a variety of growth factors, vasoactive peptides, cytokines and extracellular matrix proteins. Both murine kidney membrane and purified meprin A cleaved within the N-terminal tail of mouse BNP at position His6-Ile7. Actinonin, the most effective inhibitor for meprin A, totally blocked the mouse BNP degradation in murine kidney membranes. Interestingly, the resulting peptide BNP 7-32 appears to be accessible for degradation by NEP. Thus, the initial degradation step by meprin A is essential for the rapid BNP catabolism. As BNP elevation is discussed as a therapeutic tool in the treatment of chronic heart failure, the understanding of its metabolism is important for the development of new therapeutic strategies. Consequently, the inhibition of meprin A could be a new potential method to increase circulating BNP levels.