Adora2b Adenosine Receptor Signaling Protects during Acute Kidney Injury via Inhibition of Neutrophil-Dependent TNF-α Release

Renal ischemia is among the leading causes of acute kidney injury (AKI). Previous studies have shown that extracellular adenosine is a prominent tissue-protective cue elicited during ischemia, including signaling events through the adenosine receptor 2b (Adora2b). To investigate the functional role of Adora2b signaling in cytokine-mediated inflammatory pathways, we screened wild-type and Adora2b-deficient mice undergoing renal ischemia for expression of a range of inflammatory cytokines. These studies demonstrated a selective and robust increase of TNF-alpha levels in Adora2b-deficient mice following renal ischemia and reperfusion. Based on these findings, we next sought to understand the contribution of TNF-alpha on ischemic AKI through a combination of loss- and gain-of-function studies. Loss of TNF-alpha, through either Ab blockade or study of Tnf-alpha-deficient animals, resulted in significantly attenuated tissue injury and improved kidney function following renal ischemia. Conversely, transgenic mice with overexpression of TNF-alpha had significantly pronounced susceptibility to AKI. Furthermore, neutrophil depletion or reconstitution of Adora2b(-/-) mice with Tnf-alpha-deficient neutrophils rescued their phenotype. In total, these data demonstrate a critical role of adenosine signaling in constraining neutrophil-dependent production of TNF-alpha and implicate therapies targeting TNF-alpha in the treatment of ischemic AKI. The Journal of Immunology, 2012, 189: 4566-4573.