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SIRT1 slows the progression of lupus nephritis by regulating the NLRP3 inflammasome through ROS/TRPM2/Ca2+ channel

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Abstract

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disease associated with autoantibody formation. Lupus nephritis (LN) is one of the most severe organ manifestations of SLE. The inflammatory response is a key factor in kidney injury, and the NLRP3 inflammasome is frequently associated with the pathogenesis of LN. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD +)-dependent histone deacetylase, is a promising therapeutic target for preventing renal injury. However, the mechanism of SIRT1 in LN remains unclear. Here, we aimed to investigate the mechanism by which SIRT inhibits the NLRP3 inflammasome to slow the progression of LN. We detected the expression of SIRT1 and the infiltration of macrophages in MRL/lpr mice; the results showed that the expression of SIRT1 was decreased, and the symptoms of lupus nephritis were relieved after the use of resveratrol, which upregulated SIRT1. In vitro studies showed that after lipopolysaccharide (LPS) stimulation, SIRT1 expression decreased, and the NLRP3 inflammasome was activated. Upregulation of SIRT1 inhibits NLRP3 inflammasome activation and assembly by interfering with two signalling pathways. First, SIRT1 affects NF-κB expression, transcription, and inflammatory cytokine expression. Second, SIRT1 modulates calcium influx induced by transient receptor potential channel M2 (TRPM2), which could be partly due to the inhibition of reactive oxygen species (ROS) production. Our findings suggest that upregulated SIRT1 inhibits the NLRP3 inflammasome to slow the progression of lupus nephritis by regulating NF-κB and ROS/TRPM2/Ca2+ channels. This study reveals a new anti-inflammatory mechanism of SIRT1, suggesting that SIRT1 may be a potential therapeutic target for the prevention of LN.

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The data used to support the findings of this study are included within the article.

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Funding

This work was supported the Natural Science Foundation of Shanxi Province (No.201901D111188, 202203021221188), the Doctoral Startup Research Fund of Shanxi Medical University (No.03201403), and the Research Project Supported by Shanxi Scholarship Council of China (No.2021–079).

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Author notes

  1. Jihua Tian, Taiping Huang and Jingshu Chen have contributed equally to this work and should be considered as co-first authors.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Jihua Tian, Taiping Huang, Jingshu Chen, Jing Wang, Sijia Chang, Huanyu Xu, Jia Yang, Yuan Xue, Tingting Zhang, Weiping Fan & Yanhong Wang

  2. Department of Nephrology, The Affiliated People’s Hospital of Shanxi Medical University, Shanxi Provincial People’s Hospital, Shanxi Kidney Disease Institute, Taiyuan, 030012, Shanxi, China

    Xiaoshuang Zhou

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  1. Jihua Tian
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Contributions

All authors participated in the experimental design, data analysis, and manuscript review. TH, JC, JW, SC, HX, XZ, JY, YX, and TZ participated in the experimental operation and data analysis. JT and TH wrote the article. WF, YH revised the manuscript and provided suggestions.

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Correspondence to Jihua Tian, Weiping Fan or Yanhong Wang.

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Tian, J., Huang, T., Chen, J. et al. SIRT1 slows the progression of lupus nephritis by regulating the NLRP3 inflammasome through ROS/TRPM2/Ca2+ channel. Clin Exp Med 23, 3465–3478 (2023). https://doi.org/10.1007/s10238-023-01093-2

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