MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease [CLIP-seq]
Chronic kidney disease (CKD) complicates cisplatin-based chemotherapy of cancer patients. Here we investigate microRNA (miRNA)-regulated transcriptomic activity to unveil biological processes associated with cisplatin-induced kidney injury. Implementing chimeric-eCLIP-seq approach to a mouse model for cisplatin-induced CKD, we identify direct pairs of miRNA and their target messenger RNA in the injured kidney. We find a dedicated transcriptomic program directed by a group of miRNAs that alter metabolic pathways centered on mitochondria in the injured kidneys. Specifically, cisplatin-induced miRNA, miR-429-3p suppresses the mitochondria pathway that catalyzes branched-chain amino acid (BCAA), eventually leading to lipid peroxidation-dependent cell death, called ferroptosis. Thus, the identification of miRNA-429-3p-mediated stimulation of ferroptosis suggests a therapeutic potential for BCAA pathway modulation in ameliorating CKD and cisplatin-associated nephrotoxicity. Overall design: To investigate the miRNA effect on CKD, cisplatin induced CKD mouse and control mouse were prepared. eCLIPseq (to obtain miRNA-mRNA interaction through Ago2 complex), small RNAseq (to obtain miRNA), and RNAseq (to obtain mRNA) were performed.