Hana A Itani1, Liang Xiao1, Mohamed A Saleh1, Jing Wu1, Mark A Pilkinton1, Bethany L Dale1, Natalia R Barbaro1, Jason D Foss1, Annet Kirabo1, Kim R Montaniel1, Allison E Norlander1, Wei Chen1, Ryosuke Sato1, L Gabriel Navar1, Simon A Mallal1, Meena S Madhur1, Kenneth E Bernstein1, David G Harrison2. 1. 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. 2. 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.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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 hypertensivemice 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: Mohamed A Saleh; William G McMaster; Jing Wu; Allison E Norlander; Samuel A Funt; Salim R Thabet; Annet Kirabo; Liang Xiao; Wei Chen; Hana A Itani; Danielle Michell; Tianxiao Huan; Yahua Zhang; Satoshi Takaki; Jens Titze; Daniel Levy; David G Harrison; Meena S Madhur Journal: J Clin Invest Date: 2015-02-09 Impact factor: 14.808
Authors: Claudia Jakubzick; Emmanuel L Gautier; Sophie L Gibbings; Dorothy K Sojka; Andreas Schlitzer; Theodore E Johnson; Stoyan Ivanov; Qiaonan Duan; Shashi Bala; Tracy Condon; Nico van Rooijen; John R Grainger; Yasmine Belkaid; Avi Ma'ayan; David W H Riches; Wayne M Yokoyama; Florent Ginhoux; Peter M Henson; Gwendalyn J Randolph Journal: Immunity Date: 2013-09-05 Impact factor: 31.745
Authors: Daniel W Trott; Salim R Thabet; Annet Kirabo; Mohamed A Saleh; Hana Itani; Allison E Norlander; Jing Wu; Anna Goldstein; William J Arendshorst; Meena S Madhur; Wei Chen; Chung-I Li; Yu Shyr; David G Harrison Journal: Hypertension Date: 2014-08-04 Impact factor: 10.190
Authors: Nikhil V Kamat; Salim R Thabet; Liang Xiao; Mohamed A Saleh; Annet Kirabo; Meena S Madhur; Eric Delpire; David G Harrison; Alicia A McDonough Journal: Hypertension Date: 2015-01-19 Impact factor: 10.190
Authors: Jing Wu; Salim R Thabet; Annet Kirabo; Daniel W Trott; Mohamed A Saleh; Liang Xiao; Meena S Madhur; Wei Chen; David G Harrison Journal: Circ Res Date: 2013-12-17 Impact factor: 17.367
Authors: Annet Kirabo; Vanessa Fontana; Ana P C de Faria; Roxana Loperena; Cristi L Galindo; Jing Wu; Alfiya T Bikineyeva; Sergey Dikalov; Liang Xiao; Wei Chen; Mohamed A Saleh; Daniel W Trott; Hana A Itani; Antony Vinh; Venkataraman Amarnath; Kalyani Amarnath; Tomasz J Guzik; Kenneth E Bernstein; Xiao Z Shen; Yu Shyr; Sheau-chiann Chen; Raymond L Mernaugh; Cheryl L Laffer; Fernando Elijovich; Sean S Davies; Heitor Moreno; Meena S Madhur; Jackson Roberts; David G Harrison Journal: J Clin Invest Date: 2014-09-17 Impact factor: 14.808
Authors: David L Mattson; Hayley Lund; Chuanling Guo; Nathan Rudemiller; Aron M Geurts; Howard Jacob Journal: Am J Physiol Regul Integr Comp Physiol Date: 2013-01-30 Impact factor: 3.619
Authors: Jorge F Giani; Masahiro Eriguchi; Ellen A Bernstein; Makoto Katsumata; Xiao Z Shen; Liang Li; Alicia A McDonough; Sebastien Fuchs; Kenneth E Bernstein; Romer A Gonzalez-Villalobos Journal: Kidney Int Date: 2016-12-15 Impact factor: 10.612