NPCdc, a synthetic natriuretic peptide, is a substrate to neprilysin and enhances blood pressure-lowering induced by enalapril in 5/6 nephrectomized rats

NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influ...

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Published in:	Toxicon (Oxford) Vol. 203; pp. 30 - 39
Main Authors:	Aires, Regina Souza, Francisco da Silva Filho, Linaldo, Gomes Rebello Ferreira, Luiz Felipe, Hernandes, Marcelo Zaldini, Machado Marcondes, Marcelo Ferreira, Carmona, Adriana Karaoglanovic, Oliveira da Paixão, Ana Durce, Vieira, Leucio Duarte
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-11-2021
Subjects:	5/6 nephrectomy Angiotensin-Converting Enzyme Inhibitors - pharmacology Animals Blood Pressure Cardiorenal syndrome Enalapril Male Natriuretic peptide Natriuretic Peptides Neprilysin Peptides Peptidyl-Dipeptidase A Rats Rats, Wistar DHE NP ANP CNP AEBSF BNP RAAS HR 5/6 nephrectomy MDA RIPA TFA ANG II BSA Blood pressure FRET CKD HPLC DTPA KM ACE SDS MS Nx EDTA NPCdc Cardiorenal syndrome LEB 2 PMSF Natriuretic peptide ROS NEP Neprilysin MAP Ki PAP
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Summary:	NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 μg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P < 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 μM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes. •NPCdc is a synthetic natriuretic peptide based on the sequence of NP2Casca.•NP2Casca is isolated from Crotalus durissus cascavella snake venom.•NPCdc reduces blood pressure in addition to enalapril in nephrectomized rats.•The antioxidant effect of NPCdc involves inhibition of NADPH oxidase activity.•NPCdc presents a high affinity to NEP and inhibits its catalytic activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0041-0101 1879-3150
DOI:	10.1016/j.toxicon.2021.09.016