Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion

Abstract

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality of hepatic surgery or during liver transplantation. Previous studies had 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 via 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. Subsequent 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. Taken together, these findings implicate ENT1 in liver-protection from ischemia and reperfusion injury and suggest ENT inhibitors in the prevention or treatment of ischemic liver injury.

Equilibrative nucleoside transporter 3 depletion in β-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes

“…5A). These observations are consistent with ENT3 playing an anti-apoptotic role in β-cells, but should be interpreted with caution because dipyridamole does not fully inhibit ENT3 activity, and it also inhibits other members of the ENT family [29][30][31], including ENT1, which was also detected in MIN6 β-cells (Fig. 1A).…”

Systematic review with meta-analysis: HIF-1α attenuates liver ischemia–reperfusion injury

“…Twenty-six of included 40 articles are observational studies [14,, while the remaining are interventional studies [7,8,[15][16][17][18][43][44][45][46][47][48][49][50][51]. Nine in vitro cell culture studies were reported using various cell lines.…”

“…In animal hypoxia models, oxygen concentration was varied from 0% to 21% (asphyxia, hypoxia, and normoxia) with time spans from acute hypoxia to tolerant hypoxia. In 21 IR animal models, 11 adopted 70% liver (left and middle lobe) IR (I: 1-6 h, R: 0.5-12 h) [15,16,23,24,36,37,39,43,46,47,51], 4 liver transplantation induced IR (I: 6-24 h, R: 2 h-14 d) [18,19,44,50] …”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…The rise of cAMP, in turn, activates PKA and other downstream targets that influence gene expression [11]. Termination of adenosine signaling involves equilibrative nucleoside transporters which transports adenosine from the extracellular to the intracellular space down its concentration gradient [12]. Once within the cell, adenosine is converted to inosine via adenosine deaminase or AMP by adenosine kinase [13].…”