Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release

Almut Grenz, Jae Hwan Kim, Jessica D. Bauerle, Eunyoung Tak, Holger K. Eltzschig, Eric T. Clambey

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4566-4573
Number of pages8
JournalJournal of Immunology
Volume189
Issue number9
DOIs
Publication statusPublished - 2012 Nov 1

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Purinergic P1 Receptors
Acute Kidney Injury
Neutrophils
Ischemia
Kidney
Adenosine
Cytokines
Transgenic Mice
Reperfusion
Cues
Inhibition (Psychology)
Phenotype
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology

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Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release. / Grenz, Almut; Kim, Jae Hwan; Bauerle, Jessica D.; Tak, Eunyoung; Eltzschig, Holger K.; Clambey, Eric T.

In: Journal of Immunology, Vol. 189, No. 9, 01.11.2012, p. 4566-4573.

Research output: Contribution to journalArticle

Grenz, Almut ; Kim, Jae Hwan ; Bauerle, Jessica D. ; Tak, Eunyoung ; Eltzschig, Holger K. ; Clambey, Eric T. / Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release. In: Journal of Immunology. 2012 ; Vol. 189, No. 9. pp. 4566-4573.
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