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.

• Cell death
• cell signaling
• hepatotoxicity
• kinases
• mitochondria

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.