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Role of vitamin D/VDR nuclear translocation in down-regulation of NF-κB/NLRP3/caspase-1 axis in lupus nephritis
International Immunopharmacology ( IF 4.8 ) Pub Date : 2021-09-15 , DOI: 10.1016/j.intimp.2021.108131
Jing Huang 1 , Qi An 1 , Bo-Miao Ju 1 , Jing Zhang 1 , Ping Fan 1 , Lan He 1 , Lei Wang 2
Affiliation  

Background

Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.

Aim of the study:

This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling.

Methods

C57BL/6 mice, lupus-prone MRL/lpr mice, and VDR agonist paricacitol-treated MRL/lpr mice (300 ng/kg/mouse per dose, 5 times/week for 8 weeks from 8 weeks old) were used to assess kidney histopathology and measure proteinuria, serum anti-ds-DNA antibody and expression of NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis. We used mouse renal tubular epithelial cells (mRTECs) to identify protein–protein interactions and examine the effects of paricalcitol.

Results and Conclusion:

LN pathogenesis decreased after paricalcitol treatment. We observed a marked improvement in renal pathology and a time-dependent decrease urine protein and serum anti-dsDNA antibody levels. In 16-week-old MRL/lpr LN mice, the upregulated expression of NLRP3/caspase-1/IL-1β/IL-18 axis was significantly downregulated after paricalcitol treatment. Paricalcitol can reverse the apoptosis induced by anti-dsDNA antibody via the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis in mRTECs. Furthermore, paricalcitol suppressed NF-κB nuclear translocation by competitively binding to importin-4. In summary, the VDR agonist can alleviate LN by modulating the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis and suppressing the NF-κB nuclear translocation.



中文翻译:

维生素 D/VDR 核转位在狼疮性肾炎 NF-κB/NLRP3/caspase-1 轴下调中的作用

背景

维生素 D 受体 (VDR) 和 NLRP3 炎性体在狼疮肾炎 (LN) 发病机制中起关键作用。

研究目的:

本研究探讨了VDR激动剂对LN的治疗作用及其抑制NLRP3信号的分子机制。

方法

使用 C57BL/6 小鼠、易患狼疮的 MRL/lpr 小鼠和 VDR 激动剂帕立卡醇治疗的 MRL/lpr 小鼠(每剂 300 ng/kg/小鼠,从 8 周龄开始,每周 5 次,持续 8 周)用于评估肾脏组织病理学和测量蛋白尿、血清抗 ds-DNA 抗体和 NF-κB/NLRP3/caspase-1/IL-1β/IL-18 轴的表达。我们使用小鼠肾小管上皮细胞 (mRTECs) 来识别蛋白质-蛋白质相互作用并检查帕立骨化醇的作用。

结果和结论:

帕立骨化醇治疗后LN发病率降低。我们观察到肾脏病理学的显着改善以及尿蛋白和血清抗 dsDNA 抗体水平的时间依赖性降低。在 16 周龄 MRL/lpr LN 小鼠中,帕立骨化醇处理后,NLRP3/caspase-1/IL-1β/IL-18 轴的上调表达显着下调。Paricalcitol 可以通过 mRTECs 中的 NF-κB/NLRP3/caspase-1/IL-1β/IL-18 轴逆转抗 dsDNA 抗体诱导的细胞凋亡。此外,帕立骨化醇通过竞争性结合 importin-4 来抑制 NF-κB 核转位。总之,VDR 激动剂可以通过调节 NF-κB/NLRP3/caspase-1/IL-1β/IL-18 轴和抑制 NF-κB 核转位来缓解 LN。

更新日期:2021-09-15
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