Receptor activator of nuclear factor-κB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice.

Abstract

UNLABELLED:

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.

• Authors: Nozomu Sakai, Heather L Van Sweringen, Rebecca Schuster, John Blanchard, Justin M Burns, Amit D Tevar, Michael J Edwards, Alex B Lentsch
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 55 Issue 3 Pg. 888-97 (Mar 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22031462 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 American Association for the Study of Liver Diseases.

Chemical References

• NF-kappa B
• Osteoprotegerin
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Recombinant Proteins

Topics

• Animals
• Cells, Cultured
• Hepatocytes (drug effects, metabolism, pathology)
• In Vitro Techniques
• Kupffer Cells (drug effects, metabolism, pathology)
• Liver (blood supply, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• NF-kappa B (metabolism)
• Osteoprotegerin (metabolism)
• RANK Ligand (metabolism, pharmacology, therapeutic use)
• Receptor Activator of Nuclear Factor-kappa B (metabolism)
• Recombinant Proteins (pharmacology, therapeutic use)
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction (physiology)