Deficiency or inhibition of CD73 protects in mild kidney ischemia-reperfusion injury.
BACKGROUND
Adenosine agonists are protective in numerous models of ischemia-reperfusion injury (IRI). Pericellular adenosine is generated by the hydrolysis of extracellular adenosine triphosphate and adenosine diphosphate by the ectonucleotidase CD39 and the subsequent hydrolysis of adenosine monophosphate (AMP) by the ectonucleotidase CD73. CD39 activity is protective in kidney IRI, whereas the role of CD73 remains unclear.


METHODS
Wild-type (WT), CD73-deficient (CD73KO), CD39-transgenic (CD39tg), and hybrid CD39tg.CD73KO mice underwent right nephrectomy and unilateral renal ischemia (18-min ischemia by microvascular pedicle clamp). Renal function (serum creatinine [SCr], micromolar per liter) and histologic renal injury (score 0-9) were assessed after 24-hr reperfusion. Treatments included a CD73 inhibitor and soluble CD73.


RESULTS
Compared with WT mice (n=33, SCr 81.0, score 4.1), (1) CD73KO mice were protected (n=17, SCr 48.9, score 2.0, P<0.05), (2) CD39tg mice were protected (n=11, SCr 45.6, score 1.3, P<0.05), (3) WT mice treated with CD73 inhibitor were protected (n=9, SCr 43.3, score 1.2, P<0.05), (4) CD73KO mice reconstituted with soluble CD73 lost their protection (n=10, SCr 63.8, score 3.1, P=ns), (5) WT mice treated with soluble CD73 were not protected (n=7, SCr 78.0, score 4.1), and (6) CD39tg.CD73KO mice were protected (n=8, SCr 55.5, score 0.7, P<0.05).


CONCLUSIONS
Deficiency or inhibition of CD73 protects in kidney IRI, and CD39-mediated protection does not seem to be dependent on adenosine generation. These findings suggest that AMP may play a direct protective role in kidney IRI, which could be used in therapeutic development and organ preservation. Investigating the mechanisms by which AMP mediates protection may lead to new targets for research in kidney IRI.
Immunology Research Centre, St Vincent's Hospital, Melbourne, Victoria, Australia.
Siddharth V
SV
Rajakumar
Bo
B
Lu
Sandra
S
Crikis
Simon C
SC
Robson
Anthony J F
AJ
d'Apice
Peter J
PJ
Cowan
Karen M
KM
Dwyer
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D000249:Adenosine Monophosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001081:Apyrase / Q000235:genetics / Q000502:physiology*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000503:physiopathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
D015703:Antigens, CD; D000249:Adenosine Monophosphate; D003404:Creatinine; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen