Abstract. It was previously demonstrated that preischemic A 1 adenosine receptor (AR) activation protects renal function after ischemia-reperfusion (IR) injury in rats. The role of the A 1 AR in modulating inflammation, necrosis, and apoptosis in the kidney after IR renal injury was further characterized. C57BL/6 mice were subjected to 30 min of renal ischemia, with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine or 2-chlorocyclopentyladenosine (selective A 1 AR antagonist and agonist, respectively). Plasma creatinine levels and renal inflammation, necrosis, and apoptosis were compared 24 h after renal injury. C57BL/6 mice that had been pretreated with the A 1 AR agonist demonstrated significantly improved renal function and reduced expression of inflammatory markers, necrosis, and apoptosis 24 h after IR injury. In contrast, C57BL/6 mice that had been pretreated with the A 1 AR antagonist demonstrated significantly worsened renal function and increased expression of inflammatory markers, necrosis, and apoptosis. In conclusion, it was demonstrated that endogenous and exogenous preischemic activation of the A 1 AR protects against IR injury in vivo, through mechanisms that reduce inflammation, necrosis, and apoptosis.Acute renal failure (ARF) secondary to ischemia-reperfusion (IR) injury continues to be a significant perioperative problem. ARF is frequently complicated by many other life-threatening complications, including sepsis and multiorgan failure. The prognosis for ARF is poor (with mortality rates of approximately 50%) and has changed little in the past 40 yr (1-3).We previously demonstrated that pharmacologic adenosine receptor (AR) modulation significantly affects renal function after IR injury in rats (4 -6). In particular, we demonstrated that preischemic activation of the A 1 AR attenuated renal failure after IR injury in vivo (4). We also demonstrated the cytoprotective effects of A 1 AR activation in cultured proximal tubule cells injured by H 2 O 2 or severe ATP depletion (7,8).Modulation of AR has been demonstrated to attenuate necrosis (9), inflammation (10,11), and apoptosis (12,13) after injury. Both apoptosis and necrosis contribute significantly to the pathogenesis of ARF after IR injury (14,15). Moreover, inflammatory renal injury is a significant component of necrotic renal cell death (16,17). It remains to be determined whether the renoprotective effect of preischemic A 1 AR activation is associated with modulation of apoptosis, necrosis, and/or inflammation. Therefore, in this study, we aimed to extend our previous findings regarding the mechanisms of A 1 AR effects on renal function after IR injury. We questioned whether the protective effects of A 1 AR activation were mediated through a decrease in the inflammatory response in the kidney and whether necrotic or apoptotic cell death was attenuated. We hypothesized that preischemic activation or inhibition of A 1 AR would decrease or increase levels of inflammation markers, respectively. Moreover, we hypothesized that nec...