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Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury
journal contribution
posted on 2017-06-01, 00:00 authored by M Sashindranath, Karen DwyerKaren Dwyer, S Dezfouli, C Selan, S Crikis, B Lu, Y Yuan, M J Hickey, K Peter, S C Robson, P J Cowan, H H NandurkarKidney 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 P-selectin 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.
History
Journal
Purinergic signallingVolume
13Issue
2Pagination
259 - 265Publisher
SpringerLocation
Berlin, GermanyPublisher DOI
ISSN
1573-9538eISSN
1573-9546Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2017, SpringerUsage metrics
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No categories selectedKeywords
CD39NTPDase-1PSGL-1purinergic signallingkidney ischemia–reperfusion injuryScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyNeurosciencesNeurosciences & NeurologyKidney ischemia-reperfusion injurySELECTIN GLYCOPROTEIN LIGAND-1P-SELECTINBINDINGIDENTIFICATIONINHIBITIONPROTECTSRATS
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