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(Circulation Research. 2007;101:875.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Successive Action of Meprin A and Neprilysin Catabolizes B-Type Natriuretic Peptide

Kristin Pankow, Yong Wang, Florian Gembardt, Eberhard Krause, Xiaoou Sun, Gerd Krause, Heinz-Peter Schultheiss, Wolf-Eberhard Siems, Thomas Walther

From the Fachbereich Biologie (K.P.), Chemie, Pharmazie, Freie Universität Berlin, Germany; Leibniz-Institut für Molekulare Pharmakologie (K.P., E.K., X.S., G.K., W.-E.S.), Berlin, Germany; Department of Cardiology and Pneumology (Y.W., F.G., H.-P.S., T.W.), Campus Benjamin Franklin, Charité-Universitätsmedizin, Berlin, Germany; and Department of Pharmacology (F.G., T.W.), Erasmus Medical Center, Rotterdam, The Netherlands.

Correspondence to Thomas Walther, Charité, Campus Benjamin Franklin, Department of Cardiology and Pneumology, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail thomas.walther{at}charite.de

Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEP-knockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved biological activity. Consequently, in vivo experiments with the meprin inhibitor actinonin successfully elevated plasma BNP concentration in rats. We further demonstrated that the generation of mBNP7-32 is the prerequisite to catabolize BNP and identified NEP as the peptidase degrading the truncated BNP. Thus, the cooperative, successive action of the 2 transmembranal peptidases meprin A and NEP is crucial for rapid renal BNP inactivation. Therefore, the inhibition of meprin A could be a potent tool for increasing circulating BNP levels.

Key Words: B-type natriuretic peptide • natriuretic peptides • meprin • neutral endopeptidase • peptide degradation