The relative protective effect of CD73 deletion in renal I/RI may reflect an effect of AMP accumulation. Deletion of CD39 showed deleterious effects and administration of soluble CD39 exerted renal protection, which is partially mediated by A2AR. The protective effect conferred by apyrase suggests that supplementing CD39 NTPDase activity may be a useful therapeutic strategy in renal transplantation.

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.

Hypoxic injury occurs when the blood supply to an organ is interrupted; subsequent reperfusion halts ongoing ischemic damage but paradoxically leads to further inflammation. Together this is termed ischemia-reperfusion injury (IRI). IRI is inherent to organ transplantation and impacts both the short-and long-term outcomes of the transplanted organ. Activation of the purinergic signalling pathway is intrinsic to the pathogenesis of, and endogenous response to IRI. Therapies targeting the purinergic pathway in IRI are an attractive avenue for the improvement of transplant outcomes and the basis of ongoing research. This review aims to examine the role of adenosine receptor signalling and the ecto-nucleotidases, CD39 and CD73, in IRI, with a particular focus on renal IRI. Ischemia-reperfusion injury (IRI) is an obligatory insult in transplantation occurring at the time of organ procurement and engraftment. Ischemia is induced when blood flow to an organ is interrupted. Re-establishment of blood flow is essential to prevent ongoing hypoxic injury but paradoxically imparts further injury, termed IRI. Warm ischemia is relatively short in brain dead donors (<30 min); however, this can be prolonged in donors following cardiac arrest (up to 90 min). Furthermore, unique to transplantation is the period of cold preservation, which slows the cellular metabolic rate in order to minimize ongoing ischemic damage but which may be prolonged (extending to hours). The clinical ramifications of IRI include systemic inflammatory effects and organ dysfunction, increasing graft immunogenicity, the risk of delayed graft function, acute rejection, and chronic allograft dysfunction. There is substantial evidence implicating purinergic signalling in both the pathogenesis of and the endogenous response to IRI, and strategies targeting various aspects of the pathway may therefore be of therapeutic potential. ATP, present in relatively high concentrations intracellularly, is extruded from injured and necrotic cells into the extracellular space or released in a more controlled manner from apoptotic cells through pannexin hemi-channels and from inflammatory cells via connexin hemi-channels [1]. Upon release, extracellular ATP acts in an autocrine or paracrine manner on specific cell-surface P2 receptors belonging to two subclasses, the G protein-coupled P2Y receptors and the ATP-gated P2X nonselective cation channels [2]. ATP Keywords

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