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Circulation. 2013 Oct 15;128(16):1770-80. doi: 10.1161/CIRCULATIONAHA.113.003301. Epub 2013 Sep 18.

Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction.

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  • 1Departments of Medicine (S.C., Q.Z., C.K.R., F.R.C., N.L.H., R.M.C., S.-S.J.S., T.H.L.), Molecular Physiology and Biophysics (M.B., S.M., A.C.S., B.E.I.), and Pediatrics (L.A.P.), University of Virginia, Charlottesville; Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC (L.C., R.G.); Department of Cardiovascular and Renal Research Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark (J.H., K.M., B.L.J.); and Department of Medicine, Salem Veterans Administration, Salem, VA (S.M.M.).



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.


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.


Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.


Tmem27 protein, mouse; arginine; hypertension; salt sensitivity

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