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.

ABSTRACT: 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 si

SUBMITTER: Kimura H 

PROVIDER: S-EPMC11484893 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature