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Silibinin ameliorates cisplatin-induced acute kidney injury via activating Nfe2l1-mediated antioxidative response to suppress the ROS/MAPK signaling pathway

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Abstract

Cisplatin, a first-line chemotherapeutic agent commonly used to treat various solid tumors, induce severe adverse effects, especially nephrotoxicity, which largely limits its clinical application. However, the currently used measures to prevent nephrotoxicity are not ideal owing to the mechanisms underlying cisplatin-induced nephrotoxicity are not comprehensively understood. Herein, we examined the effects of silibinin on cisplatin-induced nephrotoxicity and found that silibinin exerted cytoprotection effects during cisplatin treatment in HEK293 cells and in a cisplatin-induced acute kidney injury (AKI) model. Mechanistically, silibinin ameliorated cisplatin-induced AKI via decreasing ROS-mediated MAPK signaling pathway activation, which was confirmed using the inhibitor N-acetylcysteine. Moreover, the protective effect of silibinin against cisplatin-induced ROS generation through the antioxidant transcription factor nuclear factor-erythroid 2-related factor 1 (Nfe2l1), rather than Nfe2l2, mediates HO1 expression. Furthermore, interference with the abundance of Nfe2l1 using siRNA or an overexpression plasmid enhanced or decreased the effect of cisplatin-induced apoptosis, respectively, in HEK293 cells. Interestingly, Nfe2l1 protein stability was more sensitive to cisplatin than that of Nfe2l2. More importantly, the mechanism that silibinin activates Nfe2l1-mediated antioxidant responses was confirmed in a cisplatin-induced AKI model. Silibinin rescued cisplatin-induced Nfe2l1 inhibition by regulating its transcription and post-translational modifications. Taken together, our results reveal a novel mechanism by which silibinin ameliorates cisplatin-induced AKI via activating Nfe2l1-mediated antioxidative response, which provides a new insights to protect patients receiving cisplatin-based cancer treatment against AKI.

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Funding

This research was funded by Sichuan Science and Technology Program (2019YJ0482), Luzhou City-Southwest Medical University Foundation (2019LZXNYDZ03), Postdoctoral Special Funding of Chongqing, and The Project of Southwest Medical University (2021ZKQN020).

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Author notes

  1. Fang Yang, Man Jia, and Chengfeng Deng have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China

    Fang Yang

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China

    Man Jia, Chengfeng Deng, Bin Xiao, Rongyang Dai & Yuancai Xiang

  3. Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China

    Yuancai Xiang

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  1. Fang Yang
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  2. Man Jia
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  4. Bin Xiao
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  5. Rongyang Dai
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Contributions

Conceptualization—YX and RD; methodology—FY, MJ, FD, and BX; resources—YX and FY; writing-original draft preparation—FY, MJ, CD, and YX; writing-review and editing—RD and YX; supervision—MJ and YX. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Rongyang Dai or Yuancai Xiang.

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10735_2022_10089_MOESM1_ESM.tif

Figure S1 The effect of cisplatin on MAPK signaling pathway in HEK293 cells. (a-d) The protein level of p-JNK, p-ERK, and p-p38 of HEK293 cells were evaluated using western blot after treatment with cisplatin (Cis, 5 μg/mL) or its vehicle control normal saline (Ctl) for indicated time periods. Supplementary file1 (TIF 22486 kb)

10735_2022_10089_MOESM2_ESM.tif

Figure S2 The effect of NAC on cisplatin induced MAPK signaling pathway activation and cell apoptosis. (a, b) HEK293 cells were pre-treated with NAC (μg/mL) for 12 h before incubated with cisplatin (Cis, 5 μg/mL) for 24 h, and then analyzed the protein levels of p-JNK, p-ERK, p-p38, PARP, and γH2AX with western blot. β-actin was used as a loading control. Supplementary file2 (TIF 16846 kb)

10735_2022_10089_MOESM3_ESM.tif

Figure S3 The effect of cisplatin on Nfe2l1 and Nfe2l2 in HEK293 cells. (a-c) HEK293 cells were treated with different concentrations of cisplatin for 24 h, then the protein levels of Nfe2l1, Nfe2l2, and HO1 were analyzed using western blot. β-actin was used as a loading control. Supplementary file3 (TIF 21383 kb)

10735_2022_10089_MOESM4_ESM.tif

Figure S4 The effect of silibinin on cisplatin-induced AKI model. (a) The HE stain of mouse kindey tissues of four groups, control (normal saline, Ctl), silibinin (Sili), cisplatin (Cis), and Sili plus Cis. (b) The concentrations of blood urea nitrogen (BUN) of these indicated groups were obtained via spectrophotometer. (c-h) The abundance of Sirt3 were analyzed using western blot after treatment with Sili, Cis, and their conbination in AKI model (c-f) and HEK293 cells (g, h). β-actin was used as a loading control. *P<0.05, **P<0.01, ***P<0.001. Supplementary file4 (TIF 82992 kb)

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Yang, F., Jia, M., Deng, C. et al. Silibinin ameliorates cisplatin-induced acute kidney injury via activating Nfe2l1-mediated antioxidative response to suppress the ROS/MAPK signaling pathway. J Mol Histol 53, 729–740 (2022). https://doi.org/10.1007/s10735-022-10089-3

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