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

Am J Physiol Renal Physiol. 2005 Apr;288(4):F722-31. doi: 10.1152/ajprenal.00378.2004. Epub 2004 Nov 23.


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(2A)Rs) mediates tissue protection. We subjected C57Bl/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl(2)MBP)] 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 Cl(2)MBP (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-beta mRNA induction. However, A(2A) agonist-mediated tissue protection is independent of IL-6 and TGF-beta 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(2A)Rs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / pathology
  • Adenosine A2 Receptor Agonists
  • Animals
  • Antimetabolites
  • Cell Line
  • Clodronic Acid
  • Cyclohexanecarboxylic Acids / pharmacology
  • Cytokines / genetics
  • Humans
  • Kidney / immunology*
  • Kidney / pathology
  • Liposomes
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Purines / pharmacology
  • RNA, Messenger / analysis
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism*
  • Reperfusion Injury / chemically induced
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / pathology
  • Transfection


  • ATL 146e
  • Adenosine A2 Receptor Agonists
  • Antimetabolites
  • Cyclohexanecarboxylic Acids
  • Cytokines
  • Liposomes
  • Purines
  • RNA, Messenger
  • Receptor, Adenosine A2A
  • Clodronic Acid