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The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in anti-Thy1 nephritis

Cellular & Molecular Immunology volume 16, pages 735–745 (2019)Cite this article

Abstract

Mesangial proliferative glomerulonephritis (MsPGN) is an inflammatory disease, but both the nature of disease progression and its regulation remain unclear. In the present study, we monitored the course of anti-Thy1 nephritis from days 1 to 5 and established gene expression profiles at each time point using microarrays to explore the development of inflammation. According to the gene expression profiles, macrophage infiltration (triggered by CCL2 activation) was evident on day 1 and enhanced inflammation over the next few days. We screened for genes with expression levels similar to CCL2 and found that the upregulation of the circadian gene albumin D-site-binding protein (DBP) was involved in CCL2 activation in mesangial cells. More importantly, CCL2 expression showed oscillatory changes similar to DBP, and DBP induced peak CCL2 expression at 16:00 a clock on day 1 in the anti-Thy1 nephritis model. We knocked down DBP through transfection with a small interfering RNA (siRNA) and used RNA sequencing to identify the DBP-regulated TNF-α-CCL2 pathway. We performed chromatin immunoprecipitation sequencing (ChIP-Seq) and the dual luciferase assay to show that DBP bound to the TRIM55 promoter, regulating gene expression and in turn controlling the TNF-α-CCL2 pathway. In conclusion, DBP-regulated circadian CCL2 expression by the TRIM55-TNF pathway in injured mesangial cells at an early stage, which promoted macrophage recruitment and in turn triggered infiltration and inflammation in a model of anti-Thy1 nephritis.

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Acknowledgements

The work was supported by grants from the National Natural Science Foundation of China (No. 81330019) and the National Basic Research Program of China (Nos. 2014CBA02005 and 2015CB553605).

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  1. These authors contributed equally: Yang Lu, Yan Mei, Lei Chen.

Authors and Affiliations

  1. Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China

    Yang Lu, Yan Mei, Lei Chen, Lingling Wu, Xu Wang, Yingjie Zhang, Bo Fu, Xizhao Chen, Yuansheng Xie, Guangyan Cai, Xueyuan Bai, Qinggang Li & Xiangmei Chen

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Correspondence to Xiangmei Chen.

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Lu, Y., Mei, Y., Chen, L. et al. The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in anti-Thy1 nephritis. Cell Mol Immunol 16, 735–745 (2019). https://doi.org/10.1038/s41423-018-0020-4

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