title: CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli.
abstract: BACKGROUND
  Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity.
  
  
  OBJECTIVE
  To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges.
  
  
  RESULTS
  We imposed repeated hypertensive challenges using either N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T(EM)) accumulated in the kidney and bone marrow. In the L-NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-γ and interleukin-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T(EM) cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow-residing T(EM) cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T(EM) cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice.
  
  
  CONCLUSIONS
  Our findings illustrate a previously undefined role of CD70 and long-lived T(EM) cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific T(EM) cells.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Hana A
authors.initials: HA
authors.lastname: Itani
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pilkinton
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Dale
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Barbaro
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Foss
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Kim R
authors.initials: KR
authors.lastname: Montaniel
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Norlander
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sato
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., L.X., M.A.S., J.W., B.L.D., J.D.F., A.K., K.R.M., A.E.N., W.C., M.S.M., D.G.H.) and Division of Infectious Diseases (M.A.P., S.A.M.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Laboratory of Cardiovascular Pharmacology, Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil (N.R.B.); Department of Physiology and Hypertension and Renal Center, School of Medicine, Tulane University, New Orleans, LA (R.S., L.G.N.); and Departments of Biomedical Sciences (K.E.B.) and Pathology and Laboratory Medicine (K.E.B.), Cedars-Sinai Medical Center, Los Angeles, CA. david.g.harrison@vanderbilt.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D053282:CD27 Ligand / Q000172:deficiency*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D053282:CD27 Ligand; D018836:Inflammation Mediators; D017673:Sodium Chloride, Dietary; D019331:NG-Nitroarginine Methyl Ester
keywords: adaptive immunity; bone marrow; immunologic memory; inflammation; interferon; interleukin 17A; kidney