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Circulation ; 128(16): 1770-80, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24048198

RESUMEN

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 AND RESULTS: 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.


Asunto(s)
Hipertensión Renal/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Peptidil-Dipeptidasa A/genética , Enzima Convertidora de Angiotensina 2 , Animales , Arginina/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Hipertensión Renal/genética , Hipertensión Renal/fisiopatología , Riñón/metabolismo , Riñón/fisiopatología , Pulmón/citología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Natriuresis/fisiología , Óxido Nítrico/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Cultivo Primario de Células , Cloruro de Sodio Dietético/farmacología , Superóxidos/metabolismo
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