title: Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction.
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.
  
  
  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.
authors.affiliation: Departments 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.).
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cechova
authors.forename: Qing
authors.initials: Q
authors.lastname: Zeng
authors.forename: Marie
authors.initials: M
authors.lastname: Billaud
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mutchler
authors.forename: Christine K
authors.initials: CK
authors.lastname: Rudy
authors.forename: Adam C
authors.initials: AC
authors.lastname: Straub
authors.forename: Liqun
authors.initials: L
authors.lastname: Chi
authors.forename: Fang R
authors.initials: FR
authors.lastname: Chan
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.forename: Kirsten
authors.initials: K
authors.lastname: Madsen
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Palmer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Sun-Sang J
authors.initials: SS
authors.lastname: Sung
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Malakauskas
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001120:Arginine / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009318:Natriuresis / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017673:Sodium Chloride, Dietary; C504407:Tmem27 protein, mouse; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: Tmem27 protein, mouse; arginine; hypertension; salt sensitivity