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Purinergic Signal. 2017 Jun;13(2):259-265. doi: 10.1007/s11302-017-9558-3. Epub 2017 Mar 25.

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

Author information

1
Australian Centre for Blood Diseases, Central Clinical School, Alfred Hospital, Monash University, Monash AMREP building, Level 1, Walkway, via The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
2
School of Medicine, Faculty of Health, Deakin University, Geelong, Australia.
3
Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
4
Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, Australia.
5
Atherothrombosis and Vascular Laboratory, Baker Heart and Diabetes Institute and Monash University, Melbourne, Australia.
6
Department of Medicine, Division of Gastroenterology, Harvard Medical School, Boston, USA.
7
Australian Centre for Blood Diseases, Central Clinical School, Alfred Hospital, Monash University, Monash AMREP building, Level 1, Walkway, via The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia. harshal.nandurkar@monash.edu.

Abstract

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 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.

KEYWORDS:

CD39; Kidney ischemia–reperfusion injury; NTPDase-1; PSGL-1; Purinergic signalling

PMID:
28343356
PMCID:
PMC5432485
DOI:
10.1007/s11302-017-9558-3
[Indexed for MEDLINE]
Free PMC Article

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