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

Abstract

Activation of A 2A adenosine receptors (A 2A Rs) protects kidneys from ischemia-reperfusion injury (IRI). A 2A Rs 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 GFPWT, A 2A -KOWT, or WTWT 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 -KOWT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WTWT chimera. ATL146e reduced the induction of IL-6, IL-1, IL-1ra, and TGF- mRNA in WTWT mice but not in A 2A -KOWT mice. Plasma creatinine was significantly greater in A 2A -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.