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

Abstract

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.

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Fig. 1: miR-483-5p expression is upregulated in cisplatin-induced AKI in C57BL/6 mice.
Fig. 2: Overexpression of miR-483-5p aggravates cisplatin-induced AKI in C57BL/6 mice.
Fig. 3: miR-483-5p overexpression aggravates cisplatin-induced AKI in TG 483 mice.
Fig. 4: Overexpression of miR-483-5p promotes apoptosis and inhibits autophagy of renal tubular cells in cisplatin-induced AKI.
Fig. 5: Overexpression of miR-483-5p promotes apoptosis and inhibits autophagy of NRK-52E cells induced by cisplatin.
Fig. 6: miR-483-5p directly targets GPX3.
Fig. 7: GPX3 overexpression rescues cisplatin-induced AKI in TG 483 mice.
Fig. 8: miR-483-5p promotes renal tubular cells apoptosis in cisplatin-induced AKI by targeting GPX3.
Fig. 9: miR-483-5p enhances oxidative stress in cisplatin-induced AKI by targeting GPX3.
Fig. 10: miR-483-5p is elevated in the serum of cancer patients after chemotherapy with cisplatin.
Fig. 11: Graphical representation illustrating the role of the miR-483-5p–mediated pathway in cisplatin-induced acute kidney injury.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request after publication.

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Acknowledgements

This work was supported by National Natural Sciences Foundation of China (31371186, 31000633, 81302230), Guangdong Natural Science Foundation (2019A1515011458, 2014A030313296), Science and Technology Program of Guangzhou, China (201607010081), the Guangdong Province Outstanding Young Teacher Training funds, the China Postdoctoral Science Foundation (2013M542159). We thank Prof. Xiaochun Bai for contributing suggestions.

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M.L. devised the conceptual ideas. Y.X., J.L., and M.L. contributed to study design. Y.X., X.Z., W.G., X.X., W.P., Y.L., and Y.Z. carried out the cell culture experiments. Y.X., J.L., and W.P. performed the animal experiments. L.L. collected the data from the cancer patients receiving chemotherapies with cisplatin. Y.X., J.L., and M.L. contributed to the discussion and interpretation of the results. M.L. took the lead in writing the paper. Y.X., C.Z., and J.L. contributed to paper editing. All authors approved the final paper.

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Correspondence to Jun Liu or Ming Li.

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All research involving human participants was approved by the Ethics Committee of Nanfang Hospital Affiliated to Southern Medical University (Guangzhou, China), and informed consent was obtained from all patients.

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Xia, Y., Pan, W., Xiao, X. et al. MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3. Lab Invest 102, 589–601 (2022). https://doi.org/10.1038/s41374-022-00737-3

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