Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells

Activation of A(2A) adenosine receptors (A(2A)Rs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow-derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A(2A)Rs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A(2A)Rs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A(2A)R-KO, or WT mice to produce GFP-->WT, A(2A)-KO-->WT, or WT-->WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A(2A)-KO mice or A(2A)-KO-->WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT-->WT chimera. ATL146e reduced the induction of IL-6, IL-1beta, IL-1ra, and TGF-alpha mRNA in WT-->WT mice but not in A(2A)-KO-->WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A(2A)R agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells.