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.
Dickey
Deborah M
DM
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Potter
Lincoln R
LR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D007976:Leupeptins; D008666:Metalloendopeptidases; D020097:Natriuretic Peptide, Brain / Q000097:blood* / Q000378:metabolism* / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D057057:Serine Proteases
D007976:Leupeptins; D011480:Protease Inhibitors; D020097:Natriuretic Peptide, Brain; D010450:Endopeptidases; D010447:Peptide Hydrolases; D057057:Serine Proteases; D008666:Metalloendopeptidases; D015260:Neprilysin; C053833:meprin A; C032854:leupeptin