The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

Abstract

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

Regulation of Vascular and Renal Function by Metabolite Receptors

“…AMP is converted to adenosine by CD73 (also known as 5′-ectonucleotidase). Although the regulation of the expression and activities of these ectonucleotidases is not clearly understood, the CD39-adenosinergic axis is considered to play critical roles in renal physiology and pathophysiology, such as TGF, renin secretion, water and sodium excretion, ischemic-reperfusion injury, and renal fibrosis (84, 98–100). CD39 is a major generator of adenosine during ischemia-reperfusion in the kidney, liver, heart, lung, brain, and bowel.…”

Extracellular nucleotide signaling in solid organ transplantation

“…In the kidney, the activity of ectonucleotidases CD39 and CD73 and resultant breakdown of extracellular ATP and enrichment of adenosine have been directly tied to graft survival . CD73 has been demonstrated to be protective in renal IRI via multiple mechanisms including enhancement of local adenosine concentration and subsequent activation of adenosine receptors.…”

The Differential Effect of Apyrase Treatment and hCD39 Overexpression on Chronic Renal Fibrosis After Ischemia-Reperfusion Injury

“…[27][28][29][30] Although suggesting that protection by apyrase was due to reduction of the extracellular ATP levels during ischemia, we cannot discount the possibility that increased adenosine levels also contributed to the protective actions of apyrase. 13 It was anticipated that accelerated metabolism of ATP and ADP by apyrase would have produced transient increase in AMP, adenosine and inosine levels. Our failure to detect this increase at the end of 23.5 minutes of ischemia may have been due to rapid metabolism of AMP by ubiquitously expressed CD73, cellular uptake of adenosine through the equilibrative nucleoside transporters and metabolism of adenosine and inosine by adenosine deaminase (ADA) and purine nucleoside phosphorylase, respectively.…”