A Novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension

Jian Dong Zhang, Mehul B. Patel, Young Soo Song, Robert Griffiths, James Burchette, Phillip Ruiz, Matthew A. Sparks, Ming Yan, David N. Howell, Jose A. Gomez, Robert F. Spurney, Thomas M. Coffman, Steven D. Crowley

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Rationale: Human clinical trials using type 1 angiotensin (AT 1) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT 1 receptors may have divergent effects on target organ damage in hypertension. Objective: We examined the role of AT 1 receptors on T lymphocytes in the pathogenesis of hypertension and its complications. Methods and Results: Deficiency of AT 1 receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4 + T cells from "T cell knockout" mice lacking AT 1 receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT 1 receptor-deficient CD4 + T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. Conclusions: The current studies identify an unexpected role for AT1 receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4 + T helper cell differentiation.

Original languageEnglish (US)
Pages (from-to)1604-1617
Number of pages14
JournalCirculation research
Volume110
Issue number12
DOIs
StatePublished - Jun 8 2012

Keywords

  • Hypertension
  • Inflammation
  • Kidney disease
  • T lymphocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Zhang, J. D., Patel, M. B., Song, Y. S., Griffiths, R., Burchette, J., Ruiz, P., Sparks, M. A., Yan, M., Howell, D. N., Gomez, J. A., Spurney, R. F., Coffman, T. M., & Crowley, S. D. (2012). A Novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension. Circulation research, 110(12), 1604-1617. https://doi.org/10.1161/CIRCRESAHA.111.261768