title: Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.
abstract: Collectrin, encoded by theTmem27gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/-) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice withTmem27Y/-kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet,Tmem27Y/-mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT andTmem27Y/-mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.
authors.affiliation: Division of Nephrology.
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Chu
authors.affiliation: Division of Nephrology.|Department of Integrated Physiology and Pharmacology, Liberty University College of Osteopathic Medicine, Lynchburg, Virginia; and.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Gigliotti
authors.affiliation: Division of Nephrology.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cechova
authors.affiliation: Division of Nephrology.
authors.forename: Gabor
authors.initials: G
authors.lastname: Bodonyi-Kovacs
authors.affiliation: Division of Nephrology.
authors.forename: Fang
authors.initials: F
authors.lastname: Chan
authors.affiliation: Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California.
authors.forename: Donna Lee
authors.initials: DL
authors.lastname: Ralph
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Howell
authors.affiliation: Division of Nephrology.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Kalantari
authors.affiliation: Cardiovascular Division, and.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.affiliation: Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: Division of Nephrology, THL4T@virginia.edu.
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation; D006973:Hypertension / Q000209:etiology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: D008562:Membrane Glycoproteins; D017673:Sodium Chloride, Dietary; C504407:Tmem27 protein, mouse; D000804:Angiotensin II
keywords: Tmem27; angiotensin converting enzyme; collectrin; hypertension; salt sensitivity