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.

Fig. 1

Mechanism of protection by adenosine in renal IRI. In IRI, ATP is released from inflammatory and apoptotic cells via connexin and pannexin hemi-channels (blue rectangle) or directly from necrotic cells into the extracellular space. ATP is converted through an enzymatic process by CD39 and CD73 on endothelial cells (EC) to adenosine (ADO), increasing its extracellular concentration ([ADO]_hi). Under hypoxic conditions, CD39 is upregulated by hypoxia-inducible specificity protein 1 (Sp1) and CD73 by hypoxia-inducible factor (HIF). Adenosine mediates its anti-inflammatory effects (brown broken arrows) via A₁R on proximal tubule cells (PTC), A_2AR on T regulatory cells (Treg) and A_2BR on endothelial cells (EC). Adenosine itself increases the expression of CD73 (single green broken arrow). During ischemia, hypoxia-inducible factor is activated which inhibits transcription of equilibrative nucleoside transporter 1 (ENT1) enabling adenosine to remain in the extracellular space. HIF also increases the expression of A₁R and A_2BR. Sphingosine kinase-1 (SK1) and sphingosine-1-phosphate receptors (S1P₁R) in the PTC augment the adenosine–A₁R interaction. In the Treg, A_2AR activation increases the expression of protein programmed-death 1(PD-1) which suppresses innate immune responses