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Blockade of aryl hydrocarbon receptor restricts omeprazole-induced chronic kidney disease

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Abstract

Chronic kidney disease (CKD) is the 16th leading cause of mortality worldwide. Clinical studies have raised that long-term use of omeprazole (OME) is associated with the morbidity of CKD. OME is commonly used in clinical practice to treat peptic ulcers and gastroesophageal reflux disease. However, the mechanism underlying renal failure following OME treatment remains mostly unknown and the rodent model of OME-induced CKD is yet to be established. We described the process of renal injury after exposure to OME in mice; the early renal injury markers were increased in renal tubular epithelial cells (RTECs). And after long-term OME treatment, the OME-induced CKD mice model was established. Herein, aryl hydrocarbon receptor (AHR) translocation appeared after exposure to OME in HK-2 cells. Then for both in vivo and in vitro, we found that Ahr-knockout (KO) and AHR small interfering RNA (siRNA) substantially alleviated the OME-induced renal function impairment and tubular cell damage. Furthermore, our data demonstrate that antagonists of AHR and CYP1A1 could attenuate OME-induced tubular cell impairment in HK-2 cells. Taken together, these data indicate that OME induces CKD through the activation of the AHR-CYP axis in RTECs. Our findings suggest that blocking the AHR-CYP1A1 pathway acts as a potential strategy for the treatment of CKD caused by OME.

Key messages

  • We provide an omeprazole-induced chronic kidney disease (CKD) mice model.

  • AHR activation and translocation process was involved in renal tubular damage and promoted the occurrence of CKD.

  • The process of omeprazole nephrotoxicity can be ameliorated by blockade of the AHR-CYP1A1 axis.

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Availability of data

The authors declare that all data supporting the findings are available within the article and Supplementary information files. The source data are available from the corresponding author. The publicly available online data about human renal transcriptomics used in this study are available in the Nephroseq database (http://v5.nephroseq.org), which ‘Ju CKD Tublnt’ dataset is analyzed in the present study.

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Acknowledgements

We thank Professor Qingjie Wang for providing technical assistance in biochemical experiments, and we also thank Professor Junhui Zhen for helping with pathologic analysis. The authors thank the investigators and staff in the laboratory for providing a favorable environment for this study.

Funding

This work was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (Grant No.82000692) and the National Natural Science Foundation of China (Grant No.82070746 and 82270775).

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Authors and Affiliations

  1. Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Nan Sun, Kuipeng Yu & Jiahui Fan

  2. Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Nan Sun, Yimeng Zhang, Lin Ding, Xin An, Fang Bai, Yanjiang Yang, Kuipeng Yu, Jiahui Fan & Xiangdong Yang

  3. Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, China

    Lei Liu

  4. Department of General Practice, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Huimin Yang

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  1. Nan Sun
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Contributions

NS: wrote the original draft. FB and YMZ: mouse colonies management. LD, XA, and YJY: collection of cell samples. KPY and JHF: conceptualization and methodology. LL and HMY: review and editing. Prof. XDY: revised and approved the final version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiangdong Yang.

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Ethics approval

All mice experiments were approved by the Institutional Animal Care and Use Committee of Shandong University and conducted following the National Institutes of Health Guide for the Care and Use of Laboratory Animals (Approval No.: KYLL-2022(ZM)-723), which is following the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

Consent to participate

The clinical data in this study, the ‘Ju CKD Tublnt’ dataset, were from the public Nephroseq database (http://v5.nephroseq.org).

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The authors declare no competing interests.

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Sun, N., Zhang, Y., Ding, L. et al. Blockade of aryl hydrocarbon receptor restricts omeprazole-induced chronic kidney disease. J Mol Med 102, 679–692 (2024). https://doi.org/10.1007/s00109-024-02429-5

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