Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension

Sonu Kashyap, Gina M. Warner, Stella P. Hartono, Rajendra Boyilla, Bruce E. Knudsen, Adeel S. Zubair, Karen Lien, Karl A Nath, Stephen C Textor, Lilach O Lerman, Joseph Peter Grande

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Original languageEnglish (US)
Pages (from-to)F372-F384
JournalAmerican Journal of Physiology - Renal Physiology
Volume310
Issue number5
DOIs
StatePublished - Mar 1 2016

Keywords

  • CCL2
  • CCR2
  • Hypertension
  • Macrophages
  • Parenchymal cells
  • Renal artery stenosis

ASJC Scopus subject areas

  • Physiology
  • Urology

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