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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/F722    most recent 00378.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Day, Y.-J. Articles by Okusa, M. D. Search for Related Content PubMed PubMed Citation Articles by Day, Y.-J. Articles by Okusa, M. D.

Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages

¹Department of Medicine and ²Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia

Submitted 12 October 2004 ; accepted in final form 19 November 2004

The role of monocytes/macrophages in the pathogenesis of ischemia-reperfusion injury (IRI) is unknown. We sought to determine whether activation of macrophage adenosine 2A (A_2A) receptors (A_2ARs) mediates tissue protection. We subjected C57Bl/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl₂MBP)] to IRI (32 min of ischemia followed by 24 h of reperfusion) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl₂MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A_2A agonists (27% of plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A_2A knockout by small interfering RNA were adoptively transferred to macrophage-depleted mice and reconstituted injury (110% of control mice); however, the increase in plasma creatinine was blocked by A_2A agonists (20% of vehicle treatment). Finally, the A_2A agonist effect on IRI was blocked in macrophage-depleted A_2A-knockout mice reconstituted with wild-type RAW 264.7 cells. RNase protection assays 24 h after IRI demonstrated that macrophages are required for IL-6 and TGF- mRNA induction. However, A_2A agonist-mediated tissue protection is independent of IL-6 and TGF- mRNA. We conclude that the full extent of IRI requires macrophages and that A_2A agonist-mediated tissue protection is independent of activation of macrophage A_2ARs.

small interfering RNA; clodronate; adoptive transfer; inflammation; acute renal failure

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