Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages.
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.
Day
Yuan-Ji
YJ
Div. of Nephrology, Box 133, Univ. of Virginia Health System, Charlottesville, VA 22908, USA.
Huang
Liping
L
Ye
Hong
H
Linden
Joel
J
Okusa
Mark D
MD
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000963:Antimetabolites; D002460:Cell Line; D004002:Clodronic Acid; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008081:Liposomes; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D014162:Transfection
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D000963:Antimetabolites; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D008081:Liposomes; D011687:Purines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D004002:Clodronic Acid