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Circ Res. 2016 Apr 15;118(8):1233-43. doi: 10.1161/CIRCRESAHA.115.308111. Epub 2016 Mar 17.

CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli.

Author information

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.

KEYWORDS:

adaptive immunity; bone marrow; immunologic memory; inflammation; interferon; interleukin 17A; kidney

PMID:
26988069
PMCID:
PMC4833561
DOI:
10.1161/CIRCRESAHA.115.308111
[Indexed for MEDLINE]
Free PMC Article

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