MicroRNA-mRNA Interactions in Cisplatin-Induced AKI to CKD

Background: Chemotherapy with cisplatin can lead to chronic kidney disease, complicating cancer prognosis. Understanding the interactions between microRNAs (miRNAs) and their target messenger RNAs (mRNAs) can shed light on the biological processes involved in cisplatin-induced kidney injury. Methods: We used small and total RNA sequencing, and chimeric-eCLIP sequencing to identify pairs of miRNAs and their target mRNAs in the kidneys of cisplatin-injured male mice. These interactions were confirmed using various methods, including database searches, RNAscope, RT-qPCR, immunofluorescence, and immunoblotting. Results: We identified 55,794 direct miRNA-mRNA interactions in the kidneys. Among the interactions, a group of cisplatin-induced miRNAs enriched with select mRNAs affects mitochondrial metabolic pathways. Specifically, the cisplatin-induced miRNAs, miR-429-3p and miR-21a-5p, suppress the pathway that breaks down branched-chain amino acids (BCAAs) in the proximal tubule, leading to ferroptotic cell death. In contrast, stimulating BCAA catabolism in the injured kidneys reduced ferroptosis and inflammation. Conclusion: In vivo renal miRNA-mRNA interaction mapping identifies the role of branched-chain amino acid catabolism in ferroptotic proximal tubular cell death. Our findings suggest potential therapeutic benefits in modulating the branched-chain amino acid pathway to alleviate nephrotoxicity. Funding: NIDDK Support