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Podocyte-specific deletion of ubiquitin carboxyl-terminal hydrolase L1 causes podocyte injury by inducing endoplasmic reticulum stress

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Abstract

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a unique component of the ubiquitin–proteasome system (UPS), which has multiple activities in maintaining intracellular ubiquitin levels. We previously reported the aberrant low expression of UCHL1 in podocytes of non-immune complex-mediated glomerulonephritis, and recent studies indicate that anti-UCHL1 antibody was responsible for the refractory minimal change disease (MCD), but the specific effect of UCHL1 to the podocytopathy has not been determined. Therefore, we generated podocyte-specific UCHL1 gene knockout (UCHL1cre/cre) rats model. Podocyte-specific UCHL1 knockout rats exhibited severe kidney damage, including segmental/global glomerulosclerosis, kidney function damage and severe proteinuria, compared with littermate control. Subsequently, by carrying out mass spectrometry analysis of isolated glomeruli of rats, abnormal protein accumulation of ECM-receptor Interaction was found in UCHL1cre/cre rats. Mechanistic studies in vivo and in vitro revealed that aberrant protein accumulation after UCHL1 deficiency induced endoplasmic reticulum (ER) stress, unfolded protein reaction (UPR) to reduce the protein level of podocyte skeleton proteins, and CHOP mediated apoptosis as well, which related to the dysfunction of the ubiquitin–proteasome system with decreased free monomeric ubiquitin level, thereby affecting protein ubiquitination and degradation. In addition, inhibition of ER stress by 4-PBA could attenuate the degree of ER stress and podocyte dysfunction. Our study indicates that UCHL1 is a potential target for preventing podocytes injury in some non-immune complex-mediated glomerulopathy.

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The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Dr. Zhihuang Zheng and Chuanlei Li for their help throughout the project.

Funding

This work was supported by the National Natural Science Foundation of China, Grant/Award (no. 82170719).

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Author notes

  1. Yuan Hu and Chenyang Qi have contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Pathology, School of Basic Medical Sciences, Fudan University, 131 Dong’an Road, Shanghai, 200032, People’s Republic of China

    Yuan Hu, Jiaoyu Shi,  Adiljan·Abdurusul, Zhonghua Zhao, Huijuan Wu & Zhigang Zhang

  2. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China

    Yuan Hu

  3. Department of Nephrology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

    Chenyang Qi

  4. Department of Surgery, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen, China

    Weiqiang Tan

  5. Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yanyong Xu

  6. Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yanyong Xu

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Contributions

HW, ZZ and YX designed the study. YH, CQ, JS and ZZ carried out experiments. WT and AA analyzed data. HW, YH and CQ drafted the paper. HW, YX and ZZ revised the paper. All the authors approved the submitted and published versions of the paper.

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Correspondence to Yanyong Xu, Huijuan Wu or Zhigang Zhang.

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The authors have no relevant financial or non-financial interests to disclose.

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The ethics governing the use and conduct of experiments on animals were strictly observed. All animal experiments were approved by the Animal Research Ethics Committee of the School of Basic Medical Sciences of Fudan University (no. 20100223).

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Hu, Y., Qi, C., Shi, J. et al. Podocyte-specific deletion of ubiquitin carboxyl-terminal hydrolase L1 causes podocyte injury by inducing endoplasmic reticulum stress. Cell. Mol. Life Sci. 80, 106 (2023). https://doi.org/10.1007/s00018-023-04747-2

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