CD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension

Yunmeng Liu; Tonya M Rafferty; Sung W Rhee; Jessica S Webber; Li Song; Benjamin Ko; Robert S Hoover; Beixiang He; Shengyu Mu

doi:10.1038/ncomms14037

CD8⁺ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension

Nat Commun. 2017 Jan 9:8:14037. doi: 10.1038/ncomms14037.

Authors

Yunmeng Liu¹, Tonya M Rafferty¹, Sung W Rhee¹, Jessica S Webber², Li Song¹, Benjamin Ko³, Robert S Hoover^{4

5}, Beixiang He^{1

2}, Shengyu Mu¹

Affiliations

¹ Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
² Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
³ Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
⁴ Department of Medicine, Division of Nephrology, Emory University, Atlanta, Georgia 30322, USA.
⁵ Research Service Atlanta, Veteran's Administration Medical Center, Decatur, Georgia 30033, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / transplantation
Chloride Channels / genetics
Chloride Channels / immunology
Chlorides / immunology
Chlorides / metabolism
Coculture Techniques
Deoxycholic Acid / administration & dosage
Epithelial Cells / drug effects
Epithelial Cells / immunology*
Epithelial Cells / pathology
Gene Expression Regulation
Hypertension / chemically induced
Hypertension / genetics*
Hypertension / immunology
Hypertension / pathology
Ion Transport
Kidney Tubules, Distal / drug effects
Kidney Tubules, Distal / immunology*
Kidney Tubules, Distal / pathology
Male
Mice
Mice, Inbred C57BL
Potassium Channels, Inwardly Rectifying / genetics
Potassium Channels, Inwardly Rectifying / immunology
Rats
Reactive Oxygen Species / immunology
Reactive Oxygen Species / metabolism
Signal Transduction
Sodium / immunology
Sodium / metabolism*
Solute Carrier Family 12, Member 3 / genetics
Solute Carrier Family 12, Member 3 / immunology
src-Family Kinases / genetics
src-Family Kinases / immunology

Substances

Chloride Channels
Chlorides
Clcnka protein, mouse
Kcnj10 (channel)
Potassium Channels, Inwardly Rectifying
Reactive Oxygen Species
Slc12a3 protein, mouse
Solute Carrier Family 12, Member 3
Deoxycholic Acid
Sodium
src-Family Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding