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DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/ reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important anti-inflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. [ABSTRACT FROM AUTHOR]

Activation of A[sub2A] adenosine receptors (A[sub2A]Rs) protects kidneys from ischemia-reperfusion injury (IRI). A[sub2A]Rs are expressed on bone marrow-derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A[sub2A]Rs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A[sub2A]Rs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A[sub2A]R-KO, or WT mice to produce GFP → WT, A[sub2A]-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[sub2A]-KO mice or A[sub2A]-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-β, IL-1ra, and TGF-α mRNA in WT → WT mice but not in A[sub2A]-KO → WT mice. Plasma creatinine was significantly greater in A[sub2A]-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A[sub2A]R agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells. [ABSTRACT FROM AUTHOR]

Activation of A2A adenosine receptors (A2ARs) 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 A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP-->WT, A2A-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 A2A-KO mice or A2A-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 A2A-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 A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells. [ABSTRACT FROM AUTHOR]