Dichloroacetate reduces cisplatin-induced apoptosis by inhibiting the JNK/14-3-3/Bax/caspase-9 pathway and suppressing caspase-8 activation via cFLIP in murine tubular cells.

Autor: Kimura H; Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-Cho, Yoshida, Fukui, 910-1193, Japan. hkimura@u-fukui.ac.jp.; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hkimura@u-fukui.ac.jp., Kamiyama K; Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-Cho, Yoshida, Fukui, 910-1193, Japan.; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Imamoto T; Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-Cho, Yoshida, Fukui, 910-1193, Japan., Takeda I; Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-Cho, Yoshida, Fukui, 910-1193, Japan., Kobayashi M; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Takahashi N; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Kasuno K; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Sugaya T; Nephrology, St Marianna University, Kawasaki, Japan., Iwano M; Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 16; Vol. 14 (1), pp. 24307. Date of Electronic Publication: 2024 Oct 16.
DOI: 10.1038/s41598-024-75229-z
Abstrakt: Cisplatin-induced injury to renal proximal tubular cells stems from mitochondrial damage-induced apoptosis and inflammation. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, a potential generator of ROS and ATP, protects against cisplatin-induced nephrotoxicity by promoting the TCA cycle. However, its effects on apoptotic pathways and ROS production in renal tubular cells remain unclear. Here, we investigated the detailed molecular mechanisms of the DCA's effects by immunoblot, RT-PCR, RNA-sequencing, and RNA-silencing in a murine renal proximal tubular (mProx) cell line and mouse kidneys. In mProx cells, DCA suppressed cisplatin-induced apoptosis by attenuating the JNK/14-3-3/Bax/caspase-9 and death receptor/ligand/caspase-8 pathways without impeding inflammatory signaling. RNA-sequencing demonstrated that DCA increased the cisplatin-reduced expression of cFLIP, a caspase-8 inactivator, and decreased the expression of almost all oxidative phosphorylation (OXPHOS) genes. DCA also increased NF-kB activation and ROS production, probably enhancing the cFLIP induction and OXPHOS gene reduction, respectively. Furthermore, cFLIP silencing weakened the DCA's anti-apoptotic effects. Finally, in mouse kidneys, DCA attenuated cisplatin-caused injuries such as functional and histological damages, caspase activation, JNK/14-3-3 activation, and cFLIP reduction. Conclusively, DCA mitigates cisplatin-induced nephrotoxicity by attenuating the JNK/14-3-3/Bax/caspase-9 pathway and inhibiting the caspase-8 pathways via cFLIP induction, probably outweighing the cisplatin plus DCA-derived cytotoxic effects including ROS.
(© 2024. The Author(s).)
Databáze: MEDLINE
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