Transgenic overexpression of CD39 protects against renal ischemia-reperfusion and transplant vascular injury

Sandra Crikis, Bo Lu, L M Murray-Segal, Carly Selan, Simon Christopher Robson, Anthony J F D'Apice, Harshal Hanumant Nandurkar, Peter J Cowan, Karen M Dwyer

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73 Citations (Scopus)

Abstract

The vascular ectonucleotidases CD39[ENTPD1 (ectonucleoside triphosphate diphosphohydrolase-1), EC 3.6.1.5] and CD73[EC 3.1.3.5] generate adenosine from extracellular nucleotides. CD39 activity is critical in determining the response to ischemia-reperfusion injury (IRI), and CD39 null mice exhibit heightened sensitivity to renal IRI. Adenosine has multiple mechanisms of action in the vasculature including direct endothelial protection, antiinflammatory and antithrombotic effects and is protective in several models of IRI. Mice transgenic for human CD39 (hCD39) have increased capacity to generate adenosine. We therefore hypothesized that hCD39 transgenic mice would be protected from renal IRI. The overexpression of hCD39 conferred protection in a model of warm renal IRI, with reduced histological injury, less apoptosis and preserved serum creatinine and urea levels. Benefit was abrogated by pretreatment with an adenosine A2A receptor antagonist. Adoptive transfer experiments showed that expression of hCD39 on either the vasculature or circulating cells mitigated IRI. Furthermore, hCD39 transgenic kidneys transplanted into syngeneic recipients after prolonged cold storage performed significantly better and exhibited less histological injury than wild-type control grafts. Thus, systemic or local strategies to promote adenosine generation and signaling may have beneficial effects on warm and cold renal IRI, with implications for therapeutic application in clinical renal transplantation.
Original languageEnglish
Pages (from-to)2586 - 2595
Number of pages10
JournalAmerican Journal of Transplantation
Volume10
Issue number12
DOIs
Publication statusPublished - 2010
Externally publishedYes

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