title: Oligoclonal CD8+ T cells play a critical role in the development of hypertension.
abstract: Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Trott
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Salim R
authors.initials: SR
authors.lastname: Thabet
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Hana
authors.initials: H
authors.lastname: Itani
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Allison E
authors.initials: AE
authors.lastname: Norlander
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Anna
authors.initials: A
authors.lastname: Goldstein
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: William J
authors.initials: WJ
authors.lastname: Arendshorst
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Li
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (D.W.T., S.R.T., A.K., M.A.S., H.I., J.W., A.G., M.S.M., W.C., D.G.H.) and Department of Pharmacology and Toxicology, Faculty of Pharmacy (M.A.S.), Mansoura University, Mansoura, Egypt; Departments of Molecular Physiology and Biophysics (A.E.N.) and Biostatistics (C.-I.L., Y.S.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill (W.J.A.). david.g.harrison@vanderbilt.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D016827:CD8 Antigens / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply / Q000276:immunology* / Q000473:pathology*; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043025:Oligoclonal Bands / Q000502:physiology*; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D018398:Homeodomain Proteins; D043025:Oligoclonal Bands; D000804:Angiotensin II; C064658:RAG-1 protein
keywords: adaptive immunity; angiotensin II; diuresis; natriuresis; receptors, antigen, T-cell