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.
Animals
Cisplatin
/ adverse effects
Mice
Apoptosis
/ drug effects
Dichloroacetic Acid
/ pharmacology
Caspase 8
/ metabolism
Caspase 9
/ metabolism
CASP8 and FADD-Like Apoptosis Regulating Protein
/ metabolism
bcl-2-Associated X Protein
/ metabolism
Kidney Tubules, Proximal
/ drug effects
Signal Transduction
/ drug effects
Reactive Oxygen Species
/ metabolism
Cell Line
Male
Kidney Tubules
/ drug effects
Apoptosis
Caspase-8
Cisplatin
Dichloroacetate
Renal tubular cells
cFLIP
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 10 2024
16 10 2024
Historique:
received:
27
04
2024
accepted:
03
10
2024
medline:
17
10
2024
pubmed:
17
10
2024
entrez:
16
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39414949
doi: 10.1038/s41598-024-75229-z
pii: 10.1038/s41598-024-75229-z
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Dichloroacetic Acid
9LSH52S3LQ
Caspase 8
EC 3.4.22.-
Caspase 9
EC 3.4.22.-
CASP8 and FADD-Like Apoptosis Regulating Protein
0
bcl-2-Associated X Protein
0
Reactive Oxygen Species
0
Casp9 protein, mouse
EC 3.4.22.-
Cflar protein, mouse
0
Casp8 protein, mouse
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
24307Subventions
Organisme : Grants-in-Aid of the Japan Society of Promotion of Science
ID : JP15K09252 to H.K.
Organisme : Grants-in-Aid of the Japan Society of Promotion of Science
ID : JP15H04836 to M.I.
Informations de copyright
© 2024. The Author(s).
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