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Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion. Hepatology 2013 Nov;58(5):1766-78



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Scopus ID

2-s2.0-84887023609   32 Citations


UNLABELLED: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality of hepatic surgery and during liver transplantation. Previous studies implicated extracellular adenosine signaling in liver protection. Based on the notion that extracellular adenosine signaling is terminated by uptake from the extracellular towards the intracellular compartment by way of equilibrative nucleoside transporters (ENTs), we hypothesized a functional role of ENTs in liver protection from ischemia. During orthotopic liver transplantation in humans, we observed higher expressional levels of ENT1 than ENT2, in conjunction with repression of ENT1 and ENT2 transcript and protein levels following warm ischemia and reperfusion. Treatment with the pharmacologic ENT inhibitor dipyridamole revealed elevations of hepatic adenosine levels and robust liver protection in a murine model of liver ischemia and reperfusion. Studies in gene-targeted mice for Ent1 or Ent2 demonstrated selective protection from liver injury in Ent1(-/-) mice. Treatment with selective adenosine receptor antagonists indicated a contribution of Adora2b receptor signaling in ENT-dependent liver protection.

CONCLUSION: These findings implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury.

Author List

Zimmerman MA, Tak E, Ehrentraut SF, Kaplan M, Giebler A, Weng T, Choi DS, Blackburn MR, Kam I, Eltzschig HK, Grenz A


Michael A. Zimmerman MD, FACS Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Equilibrative Nucleoside Transporter 1
Equilibrative-Nucleoside Transporter 2
Hypoxia-Inducible Factor 1, alpha Subunit
Liver Transplantation
Mice, Inbred C57BL
Receptor, Adenosine A2B
Reperfusion Injury
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0