Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension

Steven D. Crowley, Campbell W. Frey, Samantha K. Gould, Robert Griffiths, Phillip Ruiz, James L. Burchette, David N. Howell, Natalia Makhanova, Ming Yan, Hyung Suk Kim, Pierre Louis Tharaux, Thomas M. Coffman

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-γ and tumor necrosis factor-α and the profibrotic cytokine transforming growth factor-β. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)F515-F524
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number2
DOIs
StatePublished - Aug 2008

Keywords

  • Inflammation
  • Kidney diseases
  • T lymphocytes

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Crowley, S. D., Frey, C. W., Gould, S. K., Griffiths, R., Ruiz, P., Burchette, J. L., Howell, D. N., Makhanova, N., Yan, M., Kim, H. S., Tharaux, P. L., & Coffman, T. M. (2008). Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension. American Journal of Physiology - Renal Physiology, 295(2), F515-F524. https://doi.org/10.1152/ajprenal.00527.2007