CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. J Am Soc Nephrol 2014 Mar;25(3):547-63
Date
11/23/2013Pubmed ID
24262796Pubmed Central ID
PMC3935577DOI
10.1681/ASN.2012101014Scopus ID
2-s2.0-84896854379 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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.
Author List
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 AMESH terms used to index this publication - Major topics in bold
5'-NucleotidaseAdenosine
Animals
Diabetic Nephropathies
Endothelium
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptor, Adenosine A2B
