Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Dermatology Department Huashan Hospital, Fudan University, Shanghai, China.
Phytomedicine. 2024 Jul 25;130:155556. doi: 10.1016/j.phymed.2024.155556. Epub 2024 Mar 20.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that affects multiple organs and cause a wide range of severe clinical manifestations, including lupus nephritis (LN), which is a major risk factor for morbidity and mortality in individual with SLE. Ursolic acid (UA) is a natural compound with favorable anti-inflammatory properties and has been employed to treat multiple disease, including inflammatory diseases, diabetes, and Parkinson's disease. However, its therapeutic potential on LN and the underlying mechanisms remains unclear.
This aim of this study was to investigate the impact of UA on LN and its underlying mechanism.
MRL/lpr lupus-prone mouse model was used and UA was administered orally for 8 weeks. Dexamethasone was used as a positive control. After 8 weeks of administration, the spleen-to-body-weight ratio, renal function, urine albumin excretion, cytokines levels, and the deposition of immune complex were measured. The primary mouse glomerular mesangial cells (GMCs) and SV40-MES-13 were stimulated by lipopolysaccharide (LPS), either alone or in combination with nigericin, to establish an in vitro model. The activation of NLRP3 inflammasome were investigated both in vivo and in vitro using qRT-PCR, immunoblotting, and immunofluorescence.
Our results revealed that UA prominently alleviated LN in MRL/lpr lupus-prone mice, leading to a significant reduction in proteinuria production, infiltration of immune cells infiltration, and histopathological damage in the renal tissue. In addition, UA exerted inhibitory effects on the secretion of IL-1β, IL-18, and caspase-1, pyroptosis, and ASC speck formation in primary mouse GMCs and SV40-MES-13 cells. Furthermore, UA facilitated the degradation of NLRP3 by suppressing SUMO1-mediated SUMOylation of NLRP3.
UA possess a therapeutical effect on LN in MRL/lpr mice by enhancing the degradation of NLRP3 through inhibition of SUMO1-mediated SUMOylation of NLRP3. Our findings provide a basis for proposing UA as a potential candidate for the treatment of LN.
系统性红斑狼疮（SLE）是一种多系统自身免疫性疾病，可影响多个器官并导致广泛的严重临床表现，包括狼疮肾炎（LN），这是 SLE 患者发病率和死亡率的主要危险因素。熊果酸（UA）是一种具有良好抗炎特性的天然化合物，已被用于治疗多种疾病，包括炎症性疾病、糖尿病和帕金森病。然而，其在 LN 中的治疗潜力及其潜在机制尚不清楚。
本研究旨在探讨 UA 对 LN 的影响及其潜在机制。
使用 MRL/lpr 狼疮易感小鼠模型，口服给予 UA 8 周。地塞米松作为阳性对照。给药 8 周后，测量脾重与体重比、肾功能、尿白蛋白排泄量、细胞因子水平和免疫复合物沉积。用脂多糖（LPS）单独或与 Nigericin 联合刺激原代小鼠肾小球系膜细胞（GMC）和 SV40-MES-13 建立体外模型。用 qRT-PCR、免疫印迹和免疫荧光法在体内和体外研究 NLRP3 炎性体的激活。
我们的结果表明，UA 显著缓解了 MRL/lpr 狼疮易感小鼠的 LN，导致蛋白尿产生、免疫细胞浸润和肾组织病理损伤显著减少。此外，UA 对原代小鼠 GMC 和 SV40-MES-13 细胞中 IL-1β、IL-18 和 caspase-1、细胞焦亡和 ASC 斑点形成的分泌具有抑制作用。此外，UA 通过抑制 NLRP3 的 SUMO1 介导的 SUMO 化来促进 NLRP3 的降解。
UA 通过抑制 NLRP3 的 SUMO1 介导的 SUMO 化来促进 NLRP3 的降解，对 MRL/lpr 小鼠的 LN 具有治疗作用。我们的研究结果为提出 UA 作为治疗 LN 的潜在候选药物提供了依据。
