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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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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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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DOI: https://doi.org/10.1038/s41423-021-00763-z
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