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Chromodomain Y‐like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y‐like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 μM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg−1·d−1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

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Fig. 1: The abnormal expression of CDYL in acute kidney injury.
Fig. 2: CDYL overexpression aggravated kidney injury and pyroptosis in cisplatin-induced mice.
Fig. 3: CDYL overexpression aggravated tubular cells injury and pyroptosis in cisplatin-stimulated TCMK-1 cells.
Fig. 4: CDYL inhibitor alleviated kidney injury and decreased cell pyroptosis in cisplatin-induced AKI mice.
Fig. 5: The inhibition of CDYL improved tubular cell injury and pyroptosis in vitro.
Fig. 6: CDYL regulate the expression of FABP4.
Fig. 7: CDYL triggered pyroptosis via regulating FABP4 expression and influencing ROS production in injured kidneys.

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Data availability

All data supporting this research have been included in this manuscript and its supplementary information files. Additional data are available from the corresponding author on request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82370737 to LM and 82100775 to LL), and the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (ZYGD23015 to PF).

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  1. These authors contributed equally: Ting Xiang, Ling-zhi Li, Jin-xi Li.

Authors and Affiliations

  1. Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases, Chengdu, 610041, China

    Ting Xiang, Ling-zhi Li, Jin-xi Li, Xin-yun Chen, Fan Guo, Jing Liu, Yi-ting Wu, Liang Ma & Ping Fu

  2. West-District Outpatient Department, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Lin Lin

  3. West China School of Medicine, Sichuan University, Chengdu, 610041, China

    Rui-han Xu & Hui-ping Wang

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Contributions

LM, LZL, and TX designed the experiments. TX, LZL, JXL, XYC, YTW, XYC, and FG conducted the experiments. YTW and JXL performed the bioinformatic analyses. LL, TX, RHX, HPW, and LM analyzed the data. TX, LZL, and LM wrote the manuscript. LM, LL, and PF revised the manuscript. All authors helped to interpret the results and approved the final version of the manuscript.

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Correspondence to Lin Lin or Liang Ma.

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Xiang, T., Li, Lz., Li, Jx. et al. Chromodomain Y‐like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01345-1

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