Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis

Jian Dong Zhang, Mehul B. Patel, Robert Griffiths, Paul C. Dolber, Phillip Ruiz, Matthew A. Sparks, Johannes Stegbauer, Huixia Jin, Jose A. Gomez, Anne F. Buckley, William S. Lefler, Daian Chen, Steven D. Crowley

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53 Scopus citations

Abstract

In a wide array of kidney diseases, type 1 angiotensin (AT1) receptors are present on the immune cells that infiltrate the renal interstitium. Here, we examined the actions of AT1 receptors on macrophages in progressive renal fibrosis and found that macrophage-specific AT1 receptor deficiency exacerbates kidney fibrosis induced by unilateral ureteral obstruction (UUO). Macrophages isolated from obstructed kidneys of mice lacking AT1 receptors solely on macrophages had heightened expression of proinflammatory M1 cytokines, including IL-1. Evaluation of isolated AT1 receptor-deficient macrophages confirmed the propensity of these cells to produce exaggerated levels of M1 cytokines, which led to more severe renal epithelial cell damage via IL-1 receptor activation in coculture compared with WT macrophages. A murine kidney crosstransplantation concomitant with UUO model revealed that augmentation of renal fibrosis instigated by AT1 receptor-deficient macrophages is mediated by IL-1 receptor stimulation in the kidney. This study indicates that a key role of AT1 receptors on macrophages is to protect the kidney from fibrosis by limiting activation of IL-1 receptors in the kidney.

Original languageEnglish (US)
Pages (from-to)2198-2203
Number of pages6
JournalJournal of Clinical Investigation
Volume124
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Zhang, J. D., Patel, M. B., Griffiths, R., Dolber, P. C., Ruiz, P., Sparks, M. A., Stegbauer, J., Jin, H., Gomez, J. A., Buckley, A. F., Lefler, W. S., Chen, D., & Crowley, S. D. (2014). Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis. Journal of Clinical Investigation, 124(5), 2198-2203. https://doi.org/10.1172/JCI61368