A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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