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

Abstract

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 BNP1–32 when added individually or in combination, respectively. In contrast, neither inhibitor alone or in combination prevented the inactivation of human BNP1–32 by human kidney membranes. Leupeptin, a serine protease inhibitor, totally blocked inactivation of human BNP by human membranes, substantially blocked the inactivation of rat BNP1–32 by human membranes, but had no effect on the inactivation of rat BNP1–32 by rat kidney membranes. Purified neprilysin reduced the bioactivity of rat BNP1–32 and human BNP. Digestion with both meprin and neprilysis caused the greatest reduction in rat BNP1–32 but had no effect on the bioactivity of human BNP1–32. We conclude that meprin A does not degrade BNP in humans and should not be considered a pharmacologic target of the natriuretic peptide system.