Selective A(2A) adenosine receptor activation reduces ischemia-reperfusioninjury in rat kidney

A(2A) adenosine receptors (A(2A)-ARs) are known modulators of renal hemodyn amics and potent inhibitors of inflammation. We sought to determine whether selective activation of A(2A)-ARs protects kidneys from ischemia-reperfusi on injury. The ester derivative of DWH-146 (DWH-146e), a selective Aw agoni st, was found to be more potent and selective for A(2A)-ARs than the protot ype compound CGS-21680. Osmotic minipumps were implanted subcutaneously to infuse into rats either vehicle or DWH-146e (0.004 mu g.kg(-1).min(-1)), du ring and after ischemia-reperfusion injury. Following 24 and 48 h of reperf usion, the rise in serum creatinine and blood urea nitrogen for vehicle-tre ated rats was substantially elevated compared with DWH-146e-treated rats. H istological examination revealed widespread tubular epithelial necrosis and vascular congestion in the outer medulla of vehicle-treated compared with DWH-146e-treated animals. ZM-241385, a selective A(2A) antagonist, blocked the protective effect of DWH-146e. Delaying administration of DWH-146e unti l the initiation of reperfusion also decreased serum creatinine. We conclud e that 1) selective A(2A)-AR activation by DWH-146e reduces ischemia-reperf usion injury in rat kidneys, 2) the effect of DWH-146e is A(2A) receptor me diated, and 3) the protective effects are mediated by preventing injury dur ing the reperfusion period.