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The impact of purinergic signaling on renal ischemia-reperfusion injury

journal contribution
posted on 2008-12-27, 00:00 authored by B Lu, S V Rajakumar, S C Robson, E K F Lee, S Crikis, A J F D'Apice, P J Cowan, Karen DwyerKaren Dwyer
BACKGROUND.: Adenosine provides renovascular protection in mouse models of ischemia-reperfusion injury (I/RI) through purinergic members of the G protein-coupled receptor family, such as the adenosine 2A receptor (A2AR). Ectonucleotidases CD39 and CD73 are integral vascular and immune nucleotidases that regulate extracellular adenosine signaling. Current investigation of CD39 and CD73 in renal I/RI has primarily focused on their respective roles in ischemic preconditioning. METHODS.: In this study, we established a unilateral renal I/RI model and investigated the role of adenosine generation versus nucleotide removal in mediating protection in renal I/RI using mice deficient in CD39, CD73 or A2AR, thereby sequentially disrupting ectonucleotidase cascade and adenosinergic signaling. RESULTS.: Compared with wild-type mice, Cd73 null mice showed reduced levels of serum creatinine and urea, apoptosis of renal cells, and histologic damage after I/RI. Deletion of CD39 was associated with severe renal injury. Administration of apyrase, a soluble form of CD39, decreased global apoptosis and I/RI induced renal injury in wild-type mice. Apyrase treatment also improved renal histology to some extent in A2AR null mice. CONCLUSION.: The relative protective effect of CD73 deletion in renal I/RI may reflect an effect of AMP accumulation. Deletion of CD39 showed deleterious effects and administration of soluble CD39 exerted renal protection, which is partially mediated by A2AR. The protective effect conferred by apyrase suggests that supplementing CD39 NTPDase activity may be a useful therapeutic strategy in renal transplantation.

History

Journal

Transplantation

Volume

86

Issue

12

Pagination

1707 - 1712

Publisher

Lippincott Williams & Wilkins

Location

Philadelphia, Pa.

ISSN

0041-1337

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal