The Impact of Purinergic Signaling on Renal Ischemia-Reperfusion Injury

Lü, Bo; Rajakumar, S.; Robson, Simon C.; Lee, Eddy K. F.; Crikis, Sandra; d’Apice, Anthony J.F.; Cowan, Peter J.; Dwyer, Karen M.

doi:10.1097/tp.0b013e31819022bc

Cited by 42 publications

(40 citation statements)

References 30 publications

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“…These data indicate strong evidence for a protective effect and possible therapeutic role for CD39 in renal ischemia. 53,80 The enzyme ecto-5Ј-nucleotidase (CD73) is the rate-limiting step for production of adenosine at the extracellular space. Therefore, similar studies were conducted investigating a potential protective role for CD73 in renal ischemia and ischemic preconditioning of the kidneys.…”

Section: Adenosine Generation During Akimentioning

confidence: 99%

Adenosine Generation and Signaling during Acute Kidney Injury

Bauerle

Grenz

Kim

et al. 2011

Journal of the American Society of Nephrology

122

128

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Section: Adenosine Generation During Akimentioning

confidence: 99%

Adenosine Generation and Signaling during Acute Kidney Injury

Bauerle

Grenz

Kim

et al. 2011

Journal of the American Society of Nephrology

122

128

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“…Similarly, mice that over-expressed CD39 [49] were protected from renal IRI [42,43,50] including that in a syngeneic renal transplant model encompassing extended cold preservation [42]. More recently, protection against cardiac ischemia has been demonstrated in mice overexpressing CD39, through an A 2B R-dependent mechanism [51].…”

Section: Adenosine 1 Receptor (A 1 R)mentioning

confidence: 92%

“…The role of ectonucleotidases in IRI ENTPDase 1 (CD39) and 5′-ectonucleotidase (CD73) CD39 is the major generator of extracellular adenosine in experimental IRI, and deletion of CD39 enhances susceptibility to hypoxic injury in the kidney [42,43], liver [44], heart [45], and intestine [46] (Table 1). In the kidney, CD39 is upregulated threefold at the transcript level 90 min after IP compared with controls, whereas transcriptional levels of NTPDase 2 and 3 remain unchanged after IP [47].…”

Section: Adenosine 1 Receptor (A 1 R)mentioning

confidence: 99%

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

Roberts

Lü

Rajakumar

et al. 2012

Purinergic Signalling

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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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“…IRI leads to inflammation, kidney dysfunction, and increases graft immunogenicity and rejection. We and others have accumulated a wealth of evidence detailing the role of purinergic signalling in IRI, and strategies targeting pathways involved in purinergic signalling have shown promising results both in vitro and in vivo [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Adenosine-mediated signalling is protective in kidney IRI. CD39 overexpression protects from renal IRI via an adenosine-dependent mechanism, and CD39 −/− mice exhibit more severe renal histopathology and dysfunction than wildtype mice [1,2]. In the kidney, adenosine controls renin release, renal vascular tone and the rate of glomerular filtration.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

Sashindranath

Dwyer

Dezfouli

et al. 2017

Purinergic Signalling

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Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble Pselectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology.

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The Impact of Purinergic Signaling on Renal Ischemia-Reperfusion Injury

Cited by 42 publications

References 30 publications

Adenosine Generation and Signaling during Acute Kidney Injury

Adenosine Generation and Signaling during Acute Kidney Injury

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

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

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