title: The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury.
abstract: 1. The mechanisms of furosemide (FS) hepatotoxicity were explored in mice. Specifically, C57Bl/6 J mice were treated with 500 mg FS/kg bodyweight, and c-Jun N-terminal kinase (JNK) activation and receptor-interacting protein kinase 3 (RIP3) expression were measured by western blotting. Co-treatment with FS and the JNK inhibitor SP600125 was also performed, and FS-induced liver injury was compared in wild-type and RIP3 knockout (KO) mice. 2. JNK phosphorylation and RIP3 expression were increased in livers from the FS-treated mice as early as 6 h after treatment and persisted until at least 24 h. JNK phosphorylation was also observed in primary mouse hepatocytes and human HepaRG cells treated with FS. 3. Phosphorylated JNK translocated into mitochondria in livers, but no evidence of mitochondrial damage was observed. 4. SP600125-treated mice, SP600125 co-treated primary mouse hepatocytes and RIP3 KO mice were not protected against FS hepatotoxicity. These data show that, although JNK activation and RIP3 expression are induced by FS, neither contributes to the liver injury.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City, KS , USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.forename: Kuo
authors.initials: K
authors.lastname: Du
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Xie
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Bajt
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D005665:Furosemide / Q000009:adverse effects*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000873:Anthracenes; C432165:pyrazolanthrone; D005665:Furosemide; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D019803:Glutathione Disulfide
keywords: Cell death; cell signaling; hepatotoxicity; kinases; mitochondria