Critical Role of Neprilysin in Kidney Angiotensin Metabolism.
Circ Res
; 127(5): 593-606, 2020 08 14.
Article
em En
| MEDLINE
| ID: mdl-32418507
ABSTRACT
RATIONALE Kidney homeostasis is critically determined by the coordinated activity of the renin-angiotensin system (RAS), including the balanced synthesis of its main effector peptides Ang (angiotensin) II and Ang (1-7). The condition of enzymatic overproduction of Ang II relative to Ang (1-7) is termed RAS dysregulation and leads to cellular signals, which promote hypertension and organ damage, and ultimately progressive kidney failure. ACE2 (angiotensin-converting enzyme 2) and NEP (neprilysin) induce the alternative, and potentially reno-protective axis by enhancing Ang (1-7) production. However, their individual contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD) has not yet been elucidated. OBJECTIVE:
To examine whether NEP-mediated Ang (1-7) generation exceeds Ang II formation in the healthy kidney compared with diseased kidney. METHODS ANDRESULTS:
In this exploratory study, we used liquid chromatography-tandem mass spectrometry to measure Ang II and Ang (1-7) synthesis rates of ACE, chymase and NEP, ACE2, PEP (prolyl-endopeptidase), PCP (prolyl-carboxypeptidase) in kidney biopsy homogenates in 11 healthy living kidney donors, and 12 patients with CKD. The spatial expression of RAS enzymes was determined by immunohistochemistry. Healthy kidneys showed higher NEP-mediated Ang (1-7) synthesis than Ang II formation, thus displaying a strong preference towards the reno-protective alternative RAS axis. In contrast, in CKD kidneys higher levels of Ang II were recorded, which originated from mast cell chymase activity.CONCLUSIONS:
Ang (1-7) is the dominant RAS peptide in healthy human kidneys with NEP rather than ACE2 being essential for its generation. Severe RAS dysregulation is present in CKD dictated by high chymase-mediated Ang II formation. Kidney RAS enzyme analysis might lead to novel therapeutic approaches for CKD.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Sistema Renina-Angiotensina
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Angiotensina I
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Angiotensina II
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Neprilisina
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Insuficiência Renal Crônica
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Rim
Limite:
Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Áustria