| First Author | Grenz A | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 9 | Pages | 4566-73 |
| PubMed ID | 23028059 | Mgi Jnum | J:190594 |
| Mgi Id | MGI:5449281 | Doi | 10.4049/jimmunol.1201651 |
| Citation | Grenz A, et al. (2012) Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-alpha release. J Immunol 189(9):4566-73 |
| abstractText | 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. |
