Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice.
OBJECTIVE
Severe injury to the liver, such as that induced by toxic doses of acetaminophen, triggers a cascade of events leading to hepatocyte death. It is hypothesized that activation of the receptor for advanced glycation end products (RAGE) might contribute to acetaminophen-induced liver toxicity by virtue of its ability to generate reactive oxygen species, at least in part via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and thereby activate downstream signaling pathways leading to cellular injury.


METHODS
A model was employed in which toxic doses of acetaminophen (1125 mg/kg) were administered to C57BL/6 mice. To block RAGE, mice received murine soluble (s) RAGE, the extracellular ligand binding domain of the receptor that acts as a decoy to interrupt ligand-RAGE signaling.


RESULTS
Animals treated with sRAGE displayed increased survival compared with vehicle treatment, and markedly decreased hepatic necrosis. Consistent with an important role for RAGE-triggered oxidant stress in acetaminophen-induced injury, a significant reduction of nitrotyrosine protein adducts was observed in hepatic tissue in sRAGE-treated versus vehicle-treated mice receiving acetaminophen, in parallel with significantly increased levels of glutathione. In addition, pro-regenerative cytokines tumor necrosis factor-alpha and interleukin-6 were increased in sRAGE-treated versus vehicle-treated mice.


CONCLUSIONS
These findings implicate RAGE-dependent mechanisms in acetaminophen-induced liver damage and suggest that blockade of this pathway may impart beneficial effects in toxin-induced liver injury.
Ekong
Udeme
U
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Zeng
Shan
S
Dun
Hao
H
Feirt
Nikki
N
Guo
Jiancheng
J
Ippagunta
Nikalesh
N
Guarrera
James V
JV
Lu
Yan
Y
Weinberg
Alan
A
Qu
Wu
W
Ramasamy
Ravichandran
R
Schmidt
Ann Marie
AM
Emond
Jean C
JC