CD73-dependent generation of adenosine and endothelial adora2b signaling attenuate diabetic nephropathy

Eunyoung Tak, Douglas Ridyard, Jae Hwan Kim, Michael Zimmerman, Tilmann Werner, Xiaoxin X. Wang, Uladzimir Shabeka, Seong Wook Seo, Uwe Christians, Jost Klawitter, Radu Moldovan, Gabriela Garcia, Moshe Levi, Volker Haase, Katya Ravid, Holger K. Eltzschig, Almut Grenz

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Nucleotide phosphohydrolysis by the ecto-5′-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b-/- mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

Original languageEnglish
Pages (from-to)547-563
Number of pages17
JournalJournal of the American Society of Nephrology
Volume25
Issue number3
DOIs
Publication statusPublished - 2014 Mar 1

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Diabetic Nephropathies
Adenosine
nucleotidase
Purinergic P1 Receptors
Kidney
5'-Nucleotidase
Vascular Endothelium
Kidney Diseases
Streptozocin
Transgenic Mice
Epithelium
Nucleotides
Proteins

ASJC Scopus subject areas

  • Nephrology

Cite this

CD73-dependent generation of adenosine and endothelial adora2b signaling attenuate diabetic nephropathy. / Tak, Eunyoung; Ridyard, Douglas; Kim, Jae Hwan; Zimmerman, Michael; Werner, Tilmann; Wang, Xiaoxin X.; Shabeka, Uladzimir; Seo, Seong Wook; Christians, Uwe; Klawitter, Jost; Moldovan, Radu; Garcia, Gabriela; Levi, Moshe; Haase, Volker; Ravid, Katya; Eltzschig, Holger K.; Grenz, Almut.

In: Journal of the American Society of Nephrology, Vol. 25, No. 3, 01.03.2014, p. 547-563.

Research output: Contribution to journalArticle

Tak, E, Ridyard, D, Kim, JH, Zimmerman, M, Werner, T, Wang, XX, Shabeka, U, Seo, SW, Christians, U, Klawitter, J, Moldovan, R, Garcia, G, Levi, M, Haase, V, Ravid, K, Eltzschig, HK & Grenz, A 2014, 'CD73-dependent generation of adenosine and endothelial adora2b signaling attenuate diabetic nephropathy', Journal of the American Society of Nephrology, vol. 25, no. 3, pp. 547-563. https://doi.org/10.1681/ASN.2012101014
Tak, Eunyoung ; Ridyard, Douglas ; Kim, Jae Hwan ; Zimmerman, Michael ; Werner, Tilmann ; Wang, Xiaoxin X. ; Shabeka, Uladzimir ; Seo, Seong Wook ; Christians, Uwe ; Klawitter, Jost ; Moldovan, Radu ; Garcia, Gabriela ; Levi, Moshe ; Haase, Volker ; Ravid, Katya ; Eltzschig, Holger K. ; Grenz, Almut. / CD73-dependent generation of adenosine and endothelial adora2b signaling attenuate diabetic nephropathy. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 3. pp. 547-563.
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