Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment.
The aim of this study was to demonstrate that tacrolimus (FK506) has a hepatoprotective effect by reducing ischemia-reperfusion-induced apoptosis and necrosis, both of which lead to post-surgical liver dysfunction. An ischemia-reperfusion model and primary cultured rat hepatocytes subjected to hypoxic and reoxygenation phases, mimicking the surgical process, were used. c-Jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK1/SAPK1) activation leads to caspase 3 activation, a trigger of apoptosis. The activation status of JNK1/SAPK1 was evaluated by immunoprecipitation or Western-blotting experiments. Apoptosis was assessed by measuring caspase activation and by TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling) reaction. Necrosis was assessed histologically. Tacrolimus improved the survival rate of rats subjected to ischemia-reperfusion. After FK506 pretreatment, the liver necrosis rate was reduced, and ischemia-reperfusion-induced JNK1/SAPK1 activation and apoptosis were significantly decreased. In hypoxia-reoxygenation-subjected hepatocytes, tacrolimus reduced JNK1/SAPK1 and caspase 3 activation. In the liver, tacrolimus prevented ischemia-reperfusion-induced apoptosis and necrosis.
Crenesse
Dominique
D
Laboratoire de Physiologie, Faculté de Médecine, Université de Nice-Sophia Antipolis, Av. de Valombrose 06107 Nice 2, France. dominique.crenesse@unice.fr
Laurens
Marina
M
Heurteaux
Catherine
C
Cursio
Raffaele
R
Saint-Paul
Marie Christine
MC
Schmid-Alliana
Annie
A
Gugenheim
Jean
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D016559:Tacrolimus