IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI

Joo Yun Kim, Mihwa Kim, Ahrom Ham, Kevin M. Brown, Robert W. Greene, Vivette D. D'Agati, H. Thomas Lee

Research output: Contribution to journalArticle

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Abstract

A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targetswithin this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)- cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPAdid not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor-mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI.

Original languageEnglish (US)
Pages (from-to)1558-1570
Number of pages13
JournalJournal of the American Society of Nephrology
Volume24
Issue number10
DOIs
StatePublished - Oct 2013

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Interleukin-11
Adenosine A1 Receptors
Kidney
Interleukin-11 Receptors
Proximal Kidney Tubule
Reperfusion Injury
Adenosine A1 Receptor Agonists
Extracellular Signal-Regulated MAP Kinases
Neutralizing Antibodies
Therapeutics

ASJC Scopus subject areas

  • Nephrology

Cite this

IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI. / Kim, Joo Yun; Kim, Mihwa; Ham, Ahrom; Brown, Kevin M.; Greene, Robert W.; D'Agati, Vivette D.; Thomas Lee, H.

In: Journal of the American Society of Nephrology, Vol. 24, No. 10, 10.2013, p. 1558-1570.

Research output: Contribution to journalArticle

Kim, Joo Yun ; Kim, Mihwa ; Ham, Ahrom ; Brown, Kevin M. ; Greene, Robert W. ; D'Agati, Vivette D. ; Thomas Lee, H. / IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 10. pp. 1558-1570.
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