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

• Published in: American journal of physiology. Renal physiology Vol. 288; no. 4; pp. F722 - F731
• Main Authors: Day, Yuan-Ji, Huang, Liping, Ye, Hong, Linden, Joel, Okusa, Mark D
• Format: Journal Article
• Language: English
• Published: United States 01.04.2005
• Subjects: 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; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; Reperfusion Injury - chemically induced; Reperfusion Injury - immunology; Reperfusion Injury - pathology; RNA, Messenger - analysis; Transfection
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00378.2004

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(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.