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

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.

• Authors: Almut Grenz, Hua Zhang, Marina Hermes, Tobias Eckle, Karin Klingel, Dan Yang Huang, Christa E Müller, Simon C Robson, Hartmut Osswald, Holger K Eltzschig
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 11 Pg. 2863-73 (Sep 2007) ISSN: 1530-6860 [Electronic] United States
• PMID: 17442731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Apyrase
• CD39 antigen
• Adenosine

Topics

• Acute Kidney Injury (etiology, prevention & control)
• Adenosine (metabolism)
• Animals
• Antigens, CD (physiology)
• Apyrase (metabolism, physiology)
• Female
• Ischemic Preconditioning
• Kidney (enzymology, pathology)
• Kidney Function Tests
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Renal Artery (enzymology, pathology)
• Renal Circulation
• Reperfusion Injury (prevention & control)