Jing Huang1, Qi An1, Bo-Miao Ju1, Jing Zhang1, Ping Fan1, Lan He1, Lei Wang2. 1. Department of Rheumatism and Immunology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. 2. The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an 710004, Shaanxi, China. Electronic address: wl860806wb@163.com.
Abstract
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.
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.