Panax notoginseng saponins treat steroid-resistant lupus nephritis by inhibiting macrophage-derived exosome-induced injury in glomerular endothelial cells via the mitochondrial Autophagy-NLRP3 pathway

IF 5.4 2区医学 Q1 CHEMISTRY, MEDICINAL Journal of ethnopharmacology Pub Date : 2025-03-13 Epub Date: 2025-02-11 DOI:10.1016/j.jep.2025.119475

Feng Pan , Ying Lu , Hongtao Yang

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Abstract

Ethnopharmacological relevance

Microangiopathy represents a critical pathological characteristic of lupus nephritis (LN), with steroid resistance (SR) frequently observed among patients. Panax notoginseng saponins (PNS) has demonstrated potential in mitigating P-glycoprotein (P-gp)-mediated SR and attenuating inflammatory damage in glomerular endothelial cells (GECs) through exosomal pathways, although the precise mechanisms underlying these effects have yet to be fully elucidated.

Aim of the study

This research examines the impact of PNS on microangiopathy in steroid-resistant lupus nephritis (SR LN) and explores its involvement in the mitochondrial autophagy-NLRP3 inflammasome pathway mediated by exosomes.

Materials and methods

Steroid-resistant models were developed using methylprednisolone (MPS) in murine peritoneal macrophages (Mø). Exosomes were characterized, and biochemical markers of lupus nephritis (LN) were evaluated. Renal pathological alterations were analyzed using hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining. Mitochondrial autophagy was assessed through transmission electron microscopy. Apoptosis, mitochondrial membrane potential (MMP), P-glycoprotein (P-gp), Rhodamine-123 (Rh-123), and reactive oxygen species (ROS) were measured using flow cytometry. The expression of MDR1, PINK1/Parkin, and NLRP3 at the protein and gene levels was determined via immunoblotting and real-time PCR.

Results

Exosomes derived from SR Mø increased the expression of MDR1 and P-glycoprotein (P-gp) in GECs, reduced Rhodamine 123 (Rh-123) accumulation, inhibited mitochondrial autophagy, and activated the NLRP3 inflammasome, thereby exacerbating renal inflammation and tissue damage. Conversely, PNS were found to lower the levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), and interleukin-1 beta (IL-1β). PNS also decreased P-gp expression and increased Rh-123 accumulation. Furthermore, PNS downregulated cleaved-Caspase1 while upregulating PINK1, Parkin, Beclin-1, and the ratio of LC3II/LC3I. This dual effect of PNS reversed SR and improved renal inflammation damage.

Conclusion

PNS demonstrated an improvement in renal function and a reduction in histopathological damage, suggesting its potential therapeutic applications for LN.

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三七皂苷通过线粒体自噬- nlrp3途径抑制巨噬细胞来源的外泌体诱导的肾小球内皮细胞损伤，从而抑制类固醇抵抗性狼疮性肾炎。

民族药理学相关性：微血管病变是狼疮肾炎（LN）的一个重要病理特征，在患者中经常观察到类固醇抵抗（SR）。三七皂苷（PNS）已被证明具有通过外泌体途径减轻p -糖蛋白（P-gp）介导的SR和减轻肾小球内皮细胞（GECs）炎症损伤的潜力，尽管这些作用的确切机制尚未完全阐明。研究目的：本研究探讨PNS对类固醇抵抗性狼疮性肾炎（SR LN）微血管病变的影响，并探讨其参与外泌体介导的线粒体自噬- nlrp3炎症小体通路。材料与方法：采用甲基强的松龙（methylprednisolone， MPS）建立小鼠腹膜巨噬细胞（moo）类固醇耐药模型。对外泌体进行表征，并对狼疮性肾炎（LN）的生化标志物进行评价。采用苏木精和伊红（H&E）、马松三色、周期性酸-希夫（PAS）染色分析肾脏病理改变。透射电镜观察线粒体自噬情况。流式细胞术检测细胞凋亡、线粒体膜电位（MMP）、p -糖蛋白（P-gp）、罗丹明-123 （Rh-123）和活性氧（ROS）。通过免疫印迹和实时PCR检测MDR1、PINK1/Parkin和NLRP3在蛋白和基因水平上的表达。结果：SR moj衍生的外泌体增加了gec中MDR1和p -糖蛋白（P-gp）的表达，减少了罗丹明123 （Rh-123）的积累，抑制了线粒体自噬，激活了NLRP3炎症小体，从而加剧了肾脏炎症和组织损伤。相反，PNS可以降低促炎细胞因子的水平，包括白细胞介素-6 （IL-6）、肿瘤坏死因子-α (TNF-α)、白细胞介素-18 （IL-18）和白细胞介素-1β (IL-1β)。PNS降低了P-gp的表达，增加了Rh-123的积累。此外，PNS下调了cleaved-Caspase1，上调了PINK1、Parkin、Beclin-1和LC3II/LC3I的比值。PNS具有逆转SR和改善肾脏炎症损害的双重作用。结论：PNS可改善肾功能，减少组织病理损伤，提示其治疗LN的潜在应用。

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.