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MHC class II in renal tubules plays an essential role in renal fibrosis

Cellular & Molecular Immunology volume 18, pages 2530–2540 (2021)Cite this article

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Abstract

Immunomodulation is considered a potential therapeutic approach for chronic kidney disease (CKD). Although it has been previously reported that CD4+ T cells contribute to the development of renal fibrosis, the role of MHC class II (MHCII) in the development of renal fibrosis remains largely unknown. The present study reports that the expression of MHCII molecules in renal cortical tubules is upregulated in mouse renal fibrosis models generated by unilateral ureter obstruction (UUO) and folic acid (FA). Proximal tubule epithelial cells (PTECs) are functional antigen-presenting cells that promote the proliferation of CD4+ T cells in an MHCII-dependent manner. PTECs from mice with renal fibrosis had a stronger ability to induce T cell proliferation and cytokine production than control cells. Global or renal tubule-specific ablation of H2-Ab1 significantly alleviated renal fibrosis following UUO or FA treatment. Renal expression of profibrotic genes showed a consistent reduction in H2-Ab1 gene-deficient mouse lines. Moreover, there was a marked increase in renal tissue CD4+ T cells after UUO or FA treatment and a significant decrease following renal tubule-specific ablation of H2-Ab1. Furthermore, renal tubule-specific H2-Ab1 gene knockout mice exhibited higher proportions of regulatory T cells (Tregs) and lower proportions of Th2 cells in the UUO- or FA-treated kidneys. Finally, Immunohistochemistry (IHC) studies showed increased renal expression of MHCII and the profibrotic gene α smooth muscle actin (α-SMA) in CKD patients. Together, our human and mouse data demonstrate that renal tubular MHCII plays an important role in the pathogenesis of renal fibrosis.

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (91639201, 81390351, 91742103 and 81770868), the Medical Scientific Research Foundation of Guangdong Province (A2020260), the Natural Science Foundation of Guangdong Province of China (2018A030313134), the Guangdong Provincial Science and Technology Program (2019B030301009), the Innovation-driven Project of CSU (2020CX015), the Shenzhen Basic Research Project (JCYJ20170818141928220, JCYJ2019073015124040376), and the Shenzhen University Medical Science Cross Innovation (860000002100142).

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Authors and Affiliations

  1. Department of Physiology, Medical Research Center, Shenzhen University, Shenzhen, China

    Yunfeng Zhou & Zhaokang Luo

  2. Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Shenzhen University, Shenzhen, China

    Chenghui Liao & Zhong Huang

  3. Department of Nephrology, the First Affiliated Hospital of Shenzhen University, Shenzhen, China

    Rong Cao

  4. Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Zain Hussain

  5. Department of Internal Medicine, Shenzhen Guangming Maternity and Child Healthcare Hospital, Shenzhen, China

    Jie Wang

  6. School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China

    Yeting Zhou & Tie Chen

  7. Department of Biochemistry and Molecular Biology, Medical Research Center, Shenzhen University, Shenzhen, China

    Jie Sun

  8. Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University, Shenzhen, China

    Baohua Liu

  9. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China

    Xiaoyan Zhang & Youfei Guan

  10. National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China

    Tuo Deng

  11. Key Laboratory of Diabetes Immunology, Ministry of Education, Changsha, China

    Tuo Deng

  12. Metabolic Syndrome Research Center, Clinical Immunology Center, Central South University, Changsha, China

    Tuo Deng

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  1. Yunfeng Zhou
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Contributions

YZ, YG, and TD designed the study. YZ, ZL, and CL generated most of the data. RC, JW, YZ, TC, and JS generated some of the data. YZ, ZL, and CL analyzed the data. YZ drafted the paper. ZH, ZH, BL, and XZ performed the critical review. YZ, YG, and TD edited the paper. All authors approved the final version of the paper.

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Correspondence to Yunfeng Zhou, Youfei Guan or Tuo Deng.

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Zhou, Y., Luo, Z., Liao, C. et al. MHC class II in renal tubules plays an essential role in renal fibrosis. Cell Mol Immunol 18, 2530–2540 (2021). https://doi.org/10.1038/s41423-021-00763-z

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