Human B-type natriuretic peptide is not degraded by meprin A

B-type natriuretic peptide (BNP) combats cardiac stress by reducing blood pressure and ventricular fibrosis. Human BNP is inactivated by unknown cell surface proteases. N-terminal cleavage of mouse BNP by the renal protease meprin A was reported to increase inactivating degradation by a second protease named neprilysin. Since the sequence surrounding the meprin A cleavage site in BNP differs between species, we tested whether meprin A degrades human BNP. Using a recently developed proteolytic bioassay, the ability of various protease inhibitors to block the inactivation of BNP was measured. In rat kidney membranes, inhibitors of meprin A or neprilysin partially or completely blocked inactivation of rat BNP_1-32 when added individually or in combination, respectively. In contrast, neither inhibitor alone or in combination prevented the inactivation of human BNP_1-32 by human kidney membranes. Leupeptin, a serine protease inhibitor, totally blocked inactivation of human BNP by human membranes, substantially blocked the inactivation of rat BNP_1-32 by human membranes, but had no effect on the inactivation of rat BNP_1-32 by rat kidney membranes. Purified neprilysin reduced the bioactivity of rat BNP_1-32 and human BNP. Digestion with both meprin and neprilysis caused the greatest reduction in rat BNP_1-32 but had no effect on the bioactivity of human BNP_1-32. We conclude that meprin A does not degrade BNP in humans and should not be considered a pharmacologic target of the natriuretic peptide system.