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CHILKBP protects against podocyte injury by preserving ZO-1 expression

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Abstract

Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.

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All data generated or analyzed during this study are included in this published article and its supplementary files. Requests for materials should be addressed to YS.

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Acknowledgements

We thank Dr. Ruijun Tian of the Department of Chemistry, Southern University of Science and Technology, for help with nano-LC-MS/MS analysis; Jin Menglang in the Sun Yat-sen University for help with scanning electron microscopy and transmission electron microscopy characterization; Keyu Chen and Haiyang Liu, Shenzhen Bay Laboratory, for technical assistance. We thank SUSTech Animal Facility for the maintenance of mice and the SUSTech Core Facility for supports on the use of the confocal microscopy and transmission electron microscopy.

Funding

This work was supported, in part, by grants from the National Natural Science Foundation of China (82070728, 81900632, and 81772983); the Natural Science Foundation of Guangdong Province (2020A1515011305, 2121B1515120063 and 2017B030301018); the Shenzhen Innovation Committee of Science and Technology, China (JCYJ20190809141003834, JCYJ20200109141212325); the Stable Support Plan Program of Shenzhen Natural Science Fund (Grant No. GXWD20201230110313001 (Program Contract No.20200925153241002)).

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  1. Chen Guo and Yanyan Ding authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, 518055, China

    Chen Guo, Yanyan Ding, Aihua Yang, Yiqing Geng, Chengmin Liu, Li Zhou, Luyao Ma, Ke Jiang, Renwei Cai, Panzhu Bai, Meiling Quan, Yi Deng & Ying Sun

  2. Greater Bay Biomedical InnoCenter, Shenzhen Bay Laboratory, Shenzhen, 518055, China

    Chen Guo

  3. Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, China

    Zhe Yang

  4. National Clinical Research Center for Infectious Diseases, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, 518055, China

    Feng Hu

  5. Department of Pathology, School of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Chuanyue Wu

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  1. Chen Guo
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Contributions

Y.S. designed the study, supervised the project and wrote the manuscript; C.W. provided advice on some experiments and wrote the manuscript; C.G., Y.D., A.Y.,Y.G., C.L., L.Z., L.M., Z.Y., F.H., K.J., R.C., and P.B. performed the experiments and data analysis; Y.D. and M.Q. advised on some experiments; C.G., Y.D., A.Y., Y.G. and Y.S. take the responsibility for the integrity of the data analysis.

Corresponding authors

Correspondence to Chuanyue Wu or Ying Sun.

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All animal experiments were performed in accordance with the guidelines and regulations and approved by the Institutional Animal Care and Use Committee at the Southern University of Science and Technology of China (Approval Number: SUSTC-JY2020015). All studies for human kidney samples complied the Ethics Committee of the First Affiliated Hospital of Kunming Medical University, and informed consent was obtained from all participants in this research.

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Guo, C., Ding, Y., Yang, A. et al. CHILKBP protects against podocyte injury by preserving ZO-1 expression. Cell. Mol. Life Sci. 80, 18 (2023). https://doi.org/10.1007/s00018-022-04661-z

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