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RIP1 kinase inactivation protects against acetaminophen-induced acute liver injury in mice.
Yi, Yuguo; Zhang, Weigao; Tao, Liang; Shao, Qianchao; Xu, Qian; Chen, Yuxin; Zhang, Haibing; Zhang, Jianfa; Weng, Dan.
Afiliação
  • Yi Y; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Zhang W; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Tao L; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Shao Q; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Xu Q; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Chen Y; Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, 210008, China.
  • Zhang H; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 100864, China.
  • Zhang J; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
  • Weng D; Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. Electronic address: danweng@njust.edu.cn.
Free Radic Biol Med ; 174: 57-65, 2021 10.
Article em En | MEDLINE | ID: mdl-34324981
Many studies have investigated the role of receptor-interacting protein 1 (RIP1) kinase in acetaminophen (APAP) overdose-induced acute liver injury. However, the results were not consistent and there still remain controversies. Importantly, in these previous studies, the usage of DMSO to dissolve the RIP1 kinase inhibitor Nec-1, resulted in misleading conclusion. Our study aimed to determine the role of RIP1 kinase in APAP-induced liver injury, via genetically or pharmaceutically inhibition of RIP1 kinase activity. Our results indicated that APAP-induced liver injury was significantly attenuated in RIP1 kinase-dead (Rip1K45A/K45A) mice compared to WT control. High dosage of APAP-induced mortality was also rescued by RIP1 kinase inactivation. In agreement, RIP1 kinase inhibitor, Nec-1 which was formulated with PEG400, could efficiently alleviate APAP-induced hepatotoxicity. For the underlying mechanism, our results suggested that RIP1 kinase inactivation did not influence the hepatic GSH depletion, but significantly reduced the hepatic cell death and inflammation induced by APAP treatment. Using bone marrow transplantation model, we also demonstrated that it was RIP1 kinase activity in tissue-resident hepatic cells other than hematopoietic-derived cells mainly responsible for APAP-induced liver injury. Our study confirmed the important role of RIP1 kinase activity in APAP-induced acute liver failure.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Falência Hepática Aguda / Doença Hepática Induzida por Substâncias e Drogas Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Falência Hepática Aguda / Doença Hepática Induzida por Substâncias e Drogas Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article