MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3

• Published in: Laboratory investigation Vol. 102; no. 6; pp. 589 - 601
• Main Authors: Xia, Ying, Pan, Wenbin, Xiao, Xiao, Zhou, Xuejuan, Gu, Wenqing, Liu, Yaqin, Zhao, Yanyan, Li, Lixia, Zheng, Chenghao, Liu, Jun, Li, Ming
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2022; Nature Publishing Group
• Subjects: 13; 13/2; 631/80/82/23; 64; 64/110; 692/699/1585/4; Acute Kidney Injury - chemically induced; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Animals; Apoptosis; Apoptosis - genetics; Autophagy; Biomedical materials; Chemotherapy; Cisplatin; Cisplatin - toxicity; Diagnosis; Epithelial Cells - metabolism; Glutathione Peroxidase - metabolism; Health services; Humans; Injuries; Kidney - metabolism; Kidneys; Laboratory Medicine; Medicine; Medicine & Public Health; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Osteoarthritis; Oxidative stress; Pathology; Toxicity; Transgenic animals; Transgenic mice; Tumorigenesis
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-022-00737-3

The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted attention and concern for a long time, but the molecular mechanism of action for cisplatin is not clear. MicroRNA-483 is involved in several diseases, such as tumorigenesis and osteoarthritis, but its renal target and potential role in AKI are unknown. In this study, we explored the pathogenic role and underlying mechanism of miR-483-5p in cisplatin-induced AKI, using transgenic mice, clinical specimen, and in vitro cell line. We found that miR-483-5p was significantly upregulated by cisplatin in a cisplatin-induced mouse model, in serum samples of patients who received cisplatin therapy, and in NRK-52E cells. Overexpression of miR-483-5p in mouse kidneys by stereotactic renal injection of lentiviruses mediated miR-483-5p or generation of conditional miR-483-overexpressing transgenic mice accentuated cisplatin-induced AKI by increasing oxidative stress, promoting apoptosis, and inhibiting autophagy of tubular cells. Furthermore, our results revealed miR-483-5p directly targeted to GPX3, overexpression of which rescued cisplatin-induced AKI by inhibiting oxidative stress and apoptosis of tubular cells, but not by regulating autophagy. Collectively, miR-483-5p is upregulated by cisplatin and exacerbates cisplatin-induced AKI via negative regulation of GPX3 and contributing oxidative stress and tubular cell apoptosis. These findings reveal a pathogenic role for miR-483-5p in cisplatin-induced AKI and suggest a novel target for the diagnosis and treatment of AKI. This study reveals that miR-483-5p is upregulated by cisplatin treatment and exacerbates cisplatin-induced acute kidney injury via negative regulation of GPX3 and contributes to tubular cell apoptosis. The authors demonstrate that miR-483-5p is a key upstream mediator regulating acute kidney injury induced by cisplatin and may serve as a new target for diagnosis and therapy.