Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury.
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.
Grenz
Almut
A
Department of Pharmacology and Toxicology, Tübingen University Hospital, Tübingen, Germany.
Zhang
Hua
H
Hermes
Marina
M
Eckle
Tobias
T
Klingel
Karin
K
Huang
Dan Yang
DY
Müller
Christa E
CE
Robson
Simon C
SC
Osswald
Hartmut
H
Eltzschig
Holger K
HK
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001081:Apyrase / Q000378:metabolism / Q000502:physiology*; D005260:Female; D019194:Ischemic Preconditioning; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012077:Renal Artery / Q000201:enzymology / Q000473:pathology; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000517:prevention & control*
D015703:Antigens, CD; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine