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Receptor activator of nuclear factor‐κB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice
Author(s) -
Sakai Nozomu,
Van Sweringen Heather L.,
Schuster Rebecca,
Blanchard John,
Burns Justin M.,
Tevar Amit D.,
Edwards Michael J.,
Lentsch Alex B.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24756
Subject(s) - rankl , reperfusion injury , receptor , activator (genetics) , cytokine , inflammation , medicine , osteoprotegerin , liver injury , nf κb , endocrinology , hepatocyte , ischemia , chemistry , immunology , biochemistry , in vitro
The transcription factor nuclear factor kappaB (NF‐κB) plays diverse roles in the acute injury response to hepatic ischemia/reperfusion (I/R). Activation of NF‐κB in Kupffer cells promotes inflammation through cytokine expression, whereas activation in hepatocytes may be cell protective. The interaction of receptor activator of NF‐κB (RANK) and its ligand (RANKL) promotes NF‐κB 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‐κB 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‐κB activation. The data suggest that RANK/RANKL may be a viable therapeutic target in acute liver injury. (H epatology 2012)