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FASEB J. 2007 Sep;21(11):2863-73. Epub 2007 Apr 18.

Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury.

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1
Department of Pharmacology and Toxicology, Tübingen University Hospital, Tübingen, Germany.

Abstract

Previous studies showed increased extracellular nucleotides during renal ischemia-reperfusion. While nucleotides represent the main source for extracellular adenosine and adenosine signaling contributes to renal protection from ischemia, we hypothesized a role for ecto-nucleoside-triphosphate-diphosphohydrolases (E-NTPDases) in renal protection. We used a model of murine ischemia-reperfusion and in situ ischemic preconditioning (IP) via a hanging weight system for atraumatic renal artery occlusion. Initial studies with a nonspecific inhibitor of E-NTPDases (POM-1) revealed inhibition of renal protection by IP. We next pursued transcriptional responses of E-NTPDases (E-NTPDase1-3, and 8) to renal IP, and found a robust and selective induction of E-NTPDase1/CD39 transcript and protein. Moreover, based on clearance studies, plasma electrolytes, and renal tubular histology, IP protection was abolished in gene-targeted mice for cd39 whereas increased renal adenosine content with IP was attenuated. Furthermore, administration of apyrase reconstituted renal protection by IP in cd39-/- mice. Finally, apyrase treatment of wild-type mice resulted in increased renal adenosine concentrations and a similar degree of renal protection from ischemia as IP treatment. Taken together, these data identify CD39-dependent nucleotide phosphohydrolysis in renal protection. Moreover, the present studies suggest apyrase treatment as a novel pharmacological approach to renal diseases precipitated by limited oxygen availability.

PMID:
17442731
DOI:
10.1096/fj.06-7947com
[Indexed for MEDLINE]
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