title: CD8+T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension.
abstract: Recent studies suggest a role for T lymphocytes in hypertension. However, whether T cells contribute to renal sodium retention and salt-sensitive hypertension is unknown. Here we demonstrate that T cells infiltrate into the kidney of salt-sensitive hypertensive animals. In particular, CD8+T cells directly contact the distal convoluted tubule (DCT) in the kidneys of DOCA-salt mice and CD8+T cell-injected mice, leading to up-regulation of the Na-Cl co-transporter NCC, p-NCC and the development of salt-sensitive hypertension. Co-culture with CD8+T cells upregulates NCC in mouse DCT cells via ROS-induced activation of Src kinase, up-regulation of the K+channel Kir4.1, and stimulation of the Cl-channel ClC-K. The last event increases chloride efflux, leading to compensatory chloride influx via NCC activation at the cost of increasing sodium retention. Collectively, these findings provide a mechanism for adaptive immunity involvement in the kidney defect in sodium handling and the pathogenesis of salt-sensitive hypertension.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Yunmeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Tonya M
authors.initials: TM
authors.lastname: Rafferty
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Rhee
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Webber
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ko
authors.affiliation: Department of Medicine, Division of Nephrology, Emory University, Atlanta, Georgia 30322, USA.|Research Service Atlanta, Veteran's Administration Medical Center, Decatur, Georgia 30033, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hoover
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.|Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Beixiang
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Mu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D018118:Chloride Channels / Q000235:genetics / Q000276:immunology; D002712:Chlorides / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003840:Deoxycholic Acid / Q000008:administration & dosage; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017136:Ion Transport; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000276:immunology; D051381:Rats; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000276:immunology / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology; D000098854:Kcnj10 Channel
chemical_list: D018118:Chloride Channels; D002712:Chlorides; C489933:Clcnka protein, mouse; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D003840:Deoxycholic Acid; D012964:Sodium; D019061:src-Family Kinases