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FKBP5 deficiency attenuates calcium oxalate kidney stone formation by suppressing cell–crystal adhesion, apoptosis and macrophage M1 polarization via inhibition of NF-κB signaling

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Abstract

Surgical crushing of stones alone has not addressed the increasing prevalence of kidney stones. A promising strategy is to tackle the kidney damage and crystal aggregation inherent in kidney stones with the appropriate therapeutic target. FKBP prolyl isomerase 5 (FKBP5) is a potential predictor of kidney injury, but its status in calcium oxalate (CaOx) kidney stones is not clear. This study attempted to elucidate the role and mechanism of FKBP5 in CaOx kidney stones. Lentivirus and adeno-associated virus were used to control FKBP5 expression in a CaOx kidney stone model. Transcriptomic sequencing and immunological assays were used to analyze the mechanism of FKBP5 deficiency in CaOx kidney stones. The results showed that FKBP5 deficiency reduced renal tubular epithelial cells (RTEC) apoptosis and promoted cell proliferation by downregulating BOK expression. It also attenuated cell–crystal adhesion by downregulating the expression of CDH4. In addition, it inhibited M1 polarization and chemotaxis of macrophages by suppressing CXCL10 expression in RTEC. Moreover, the above therapeutic effects were exerted by inhibiting the activation of NF-κB signaling. Finally, in vivo experiments showed that FKBP5 deficiency attenuated stone aggregation and kidney injury in mice. In conclusion, this study reveals that FKBP5 deficiency attenuates cell–crystal adhesion, reduces apoptosis, promotes cell proliferation, and inhibits macrophage M1 polarization and chemotaxis by inhibiting NF-κB signaling. This provides a potential therapeutic target for CaOx kidney stones.

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Data availability

The raw data of RNA-seq were shown in Supplementary Information 2. Other data will be made available on request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82070723) and (No. 82270797).

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Author notes

  1. Qianlin Song, Chao Song and Xin Chen contributed equally to this work and shared the first authorship.

Authors and Affiliations

  1. Department of Urology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, Hubei, People’s Republic of China

    Qianlin Song, Chao Song, Yunhe Xiong, Wenbiao Liao & Sixing Yang

  2. Central Laboratory, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, Hubei, People’s Republic of China

    Qianlin Song & Xin Chen

  3. Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Jiefang Road 238, Wuhan, 430060, Hubei, People’s Republic of China

    Xin Chen

  4. School of Power and Mechanical Engineering, The Institute of Technological Science, Wuhan University, South Donghu Road 8, Wuhan, 430072, Hubei, People’s Republic of China

    Lijun Li & Longjian Xue

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  1. Qianlin Song
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  2. Chao Song
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Contributions

SXY, LJX, and QLS designed the research and wrote the manuscript; QLS, CS, XC, LJL, and WBL performed the experiments; CS, WBL, and LJX analyzed data; QLS, XC, CS, and YHX performed the animal model, and performed critical reading/editing of the manuscript; SXY and LJX supervised the study.

Corresponding authors

Correspondence to Xin Chen, Longjian Xue or Sixing Yang.

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The authors have declared that no conflict of interest exists.

Ethical approval

The animal experiments in this study were approved by the Animal Ethics Committee of the Renmin Hospital of Wuhan University (Issue No. 20221008A).

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Song, Q., Song, C., Chen, X. et al. FKBP5 deficiency attenuates calcium oxalate kidney stone formation by suppressing cell–crystal adhesion, apoptosis and macrophage M1 polarization via inhibition of NF-κB signaling. Cell. Mol. Life Sci. 80, 301 (2023). https://doi.org/10.1007/s00018-023-04958-7

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  • DOI: https://doi.org/10.1007/s00018-023-04958-7

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