Receptor activator of nuclear factor-kappaB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice.
Publication year
2012Source
Hepatology, 55, 3, (2012), pp. 888-897ISSN
Annotation
1 maart 2012
Publication type
Article / Letter to editor

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Organization
Surgery
Journal title
Hepatology
Volume
vol. 55
Issue
iss. 3
Page start
p. 888
Page end
p. 897
Subject
NCEBP 2: Evaluation of complex medical interventionsAbstract
The transcription factor nuclear factor kappaB (NF-kappaB) plays diverse roles in the acute injury response to hepatic ischemia/reperfusion (I/R). Activation of NF-kappaB in Kupffer cells promotes inflammation through cytokine expression, whereas activation in hepatocytes may be cell protective. The interaction of receptor activator of NF-kappaB (RANK) and its ligand (RANKL) promotes NF-kappaB activation; however, this ligand-receptor system has not been studied in acute liver injury. In the current study, we sought to determine if RANK and RANKL were important in the hepatic response to I/R. Mice were subjected to partial hepatic ischemia followed by reperfusion. In some experiments, mice received recombinant RANKL or neutralizing antibodies to RANKL 1 hour prior to surgery or at reperfusion to assess the role of RANK/RANKL signaling during I/R injury. RANK was constitutively expressed in the liver and was not altered by I/R. RANK was strongly expressed in hepatocytes and very weakly expressed in Kupffer cells. Serum RANKL concentrations increased after I/R and peaked 4 hours after reperfusion. Serum levels of osteoprotegerin (OPG), a decoy receptor for RANKL, steadily increased over the 8-hour period of reperfusion. Treatment with RANKL, before ischemia or at reperfusion, increased hepatocyte NF-kappaB activation and significantly reduced liver injury. These beneficial effects occurred without any effect on cytokine expression or liver inflammation. Treatment with anti-RANKL antibodies had no effect on liver I/R injury. CONCLUSION: During the course of injury, endogenous OPG appears to suppress the effects of RANKL. However, exogenous administration of RANKL, given either prophylactically or postinjury, reduces liver injury in a manner associated with increased hepatocyte NF-kappaB activation. The data suggest that RANK/RANKL may be a viable therapeutic target in acute liver injury.
This item appears in the following Collection(s)
- Academic publications [202923]
- Faculty of Medical Sciences [80072]
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