期刊
CIRCULATION
卷 128, 期 16, 页码 1770-1780出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.003301
关键词
arginine; hypertension; salt sensitivity; Tmem27 protein; mouse
资金
- Division of Nephrology at the University of Virginia
- Norman S. Coplan Extramural Grant through Satellite Healthcare
- Novo Nordisk Fonden [NNF13OC0006215] Funding Source: researchfish
Background Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing approximate to 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.
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