title: Increased expression of renal neutral endopeptidase in severe heart failure.
abstract: The enzyme neutral endopeptidase (NEP; EC 3.4.24.11) cleaves several vasoactive peptides such as the atrial natriuretic peptide (ANP). ANP is a hormone of cardiac origin with diuretic and natriuretic actions. Despite elevated circulating levels of ANP, congestive heart failure (CHF) is characterized by progressive sodium and water retention. In order to elucidate the loss of natriuretic and diuretic properties of ANP in CHF we analyzed activity, protein concentrations, mRNA and immunostaining of NEP in kidneys of different models of severe CHF in the rat.CHF was induced by either aortocaval shunt, aortic banding or myocardial infarction in the rat. All models were defined by increased left ventricular end-diastolic pressure and decreased contractility. The diminished effectiveness of ANP was reflected by reduced cGMP/ANP ratio in animals with shunt or infarction. Renal NEP activity was increased in rats with aortocaval shunt (203 +/- 7%, p < 0.001), aortic banding (184 +/- 11%, p < 0.001) and infarction (149 +/- 10%, p < 0.005). Western blot analysis revealed a significant increase in renal NEP protein content in two models of CHF (shunt: 214 +/- 57%, p < 0.05; infarction: 310 +/- 53 %, p < 0.01). The elevated protein expression was paralleled by a threefold increase in renal NEP-mRNA level in the infarction model. The increased renal NEP protein expression and activity may lead to enhanced degradation of ANP and may contribute to the decreased renal response to ANP in heart failure. Thus, the capacity to counteract sodium and water retention, would be diminished. The increased renal NEP activity may therefore be a hitherto unknown factor in the progression of CHF.
authors.affiliation: Medical Science Department, Boehringer Ingelheim Pharma KG, 55216 Ingelheim am Rhein, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Knecht
authors.forename: Ines
authors.initials: I
authors.lastname: Pagel
authors.forename: Thomas
authors.initials: T
authors.lastname: Langenickel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Philipp
authors.forename: Michaela
authors.initials: M
authors.lastname: Scheuermann-Freestone
authors.forename: Thomas
authors.initials: T
authors.lastname: Willnow
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Kristof
authors.initials: K
authors.lastname: Graf
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Roland
authors.initials: R
authors.lastname: Willenbrock
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001483:Base Sequence; D006152:Cyclic GMP / Q000652:urine; D017931:DNA Primers; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006439:Hemodynamics; D007668:Kidney / Q000201:enzymology*; D008297:Male; D015260:Neprilysin / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP