title: Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release.
abstract: 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-α levels in Adora2b-deficient mice following renal ischemia and reperfusion. Based on these findings, we next sought to understand the contribution of TNF-α on ischemic AKI through a combination of loss- and gain-of-function studies. Loss of TNF-α, through either Ab blockade or study of Tnf-α-deficient animals, resulted in significantly attenuated tissue injury and improved kidney function following renal ischemia. Conversely, transgenic mice with overexpression of TNF-α had significantly pronounced susceptibility to AKI. Furthermore, neutrophil depletion or reconstitution of Adora2b(-/-) mice with Tnf-α-deficient neutrophils rescued their phenotype. In total, these data demonstrate a critical role of adenosine signaling in constraining neutrophil-dependent production of TNF-α and implicate therapies targeting TNF-α in the treatment of ischemic AKI.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Bauerle
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Tak
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D007511:Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015424:Reperfusion / Q000379:methods; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*
chemical_list: D043704:Receptor, Adenosine A2B; D014409:Tumor Necrosis Factor-alpha