Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction.
Circulation
; 128(16): 1770-80, 2013 Oct 15.
Article
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| MEDLINE
| ID: mdl-24048198
ABSTRACT
BACKGROUND:
Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation. METHODS ANDRESULTS:
Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice.CONCLUSIONS:
Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Glicoproteínas de Membrana
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Peptidil-Dipeptidasa A
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Óxido Nítrico Sintasa de Tipo III
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Hipertensión Renal
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
Circulation
Año:
2013
Tipo del documento:
Article