Huang Jing, An Qi, Ju Bo-Miao, Zhang Jing, Fan Ping, He Lan, Wang Lei
Department of Rheumatism and Immunology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an 710004, Shaanxi, China.
Int Immunopharmacol. 2021 Nov;100:108131. doi: 10.1016/j.intimp.2021.108131. Epub 2021 Sep 15.
Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling.
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.
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.
维生素D受体（VDR）和NLRP3炎性小体在狼疮性肾炎（LN）发病机制中起关键作用。
本研究探讨VDR激动剂对LN的治疗作用及其抑制NLRP3信号传导的分子机制。
使用C57BL/6小鼠、狼疮易感MRL/lpr小鼠以及用VDR激动剂帕立骨化醇治疗的MRL/lpr小鼠（每剂量300 ng/kg/小鼠，从8周龄开始每周5次，共8周）来评估肾脏组织病理学，并测量蛋白尿、血清抗双链DNA抗体以及NF-κB/NLRP3/半胱天冬酶-1/白细胞介素-1β/白细胞介素-18轴的表达。我们使用小鼠肾小管上皮细胞（mRTECs）来鉴定蛋白质-蛋白质相互作用并检测帕立骨化醇的作用。
帕立骨化醇治疗后LN发病机制减轻。我们观察到肾脏病理学有显著改善，尿蛋白和血清抗双链DNA抗体水平呈时间依赖性下降。在16周龄的MRL/lpr LN小鼠中，帕立骨化醇治疗后NLRP3/半胱天冬酶-1/白细胞介素-1β/白细胞介素-18轴上调的表达显著下调。帕立骨化醇可通过NF-κB/NLRP3/半胱天冬酶-1/白细胞介素-1β/白细胞介素-18轴逆转抗双链DNA抗体诱导的mRTECs凋亡。此外，帕立骨化醇通过与输入蛋白-4竞争性结合来抑制NF-κB核转位。总之，VDR激动剂可通过调节NF-κB/NLRP3/半胱天冬酶-1/白细胞介素-1β/白细胞介素-18轴并抑制NF-κB核转位来减轻LN。
