Lithium exacerbates hepatic ischemia/reperfusion injury by inhibiting GSK-3β/NF-κB-mediated protective signaling in mice.
Lithium (an inhibitor of GSK-3β activity) has beneficial effects on ischemia/reperfusion (I/R) injury in the central nervous system, heart and kidney. However, the role of lithium in hepatic I/R injury is unknown. The aim of this study was to assess the effects of lithium on hepatic I/R injury in a mouse model of partial hepatic I/R. Previous studies showed that lithium chloride (LiCl) can phosphorylate residue Ser9, inhibit GSK-3β activity, and improve I/R injury in other organs. In the present study, mice were pretreated with either vehicle or LiCl, which had similar effects on GSK-3β activity. Surprisingly, treatment with LiCl significantly exacerbated hepatic I/R injury, which was determined by serological and histological analyses. Acute and chronic LiCl treatment caused serious damage in hepatic I/R injury, including increased apoptosis and oxidative stress. To gain insight into the mechanism involved in this damage, the activity of nuclear factor-κB (NF-κB) (GSK-3β can regulate the transcriptional complex of NF-κB) was analyzed, which revealed that LiCl treatment significantly down-regulated the activity of NF-κB. The NF-κB-mediated protective genes were then further evaluated, including anti-apoptotic genes (RAF2, cIAP 2, Bfl-1 and cFLIP) and the antioxidant gene MnSOD. The expression of these protective genes was obviously suppressed compared with the vehicle group. Taken together, these findings show that lithium exacerbates hepatic I/R injury by suppressing the expression of GSK-3β/NF-κB-mediated protective genes.
Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Yongxiang
Y
Xia
Jianhua
J
Rao
Aihua
A
Yao
Feng
F
Zhang
Guoqiang
G
Li
Xuehao
X
Wang
Ling
L
Lu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D018021:Lithium Chloride / Q000633:toxicity*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D013997:Time Factors
C096816:BCL2-related protein A1; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D047992:TNF Receptor-Associated Factor 2; D012694:Serine; D013482:Superoxide Dismutase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D018021:Lithium Chloride