补体因子B抑制剂LNP023介导AMPK/mTOR对狼疮肾炎自噬和氧化应激的影响及其机制

The Kaohsiung journal of medical sciences Pub Date : 2024-11-01 Epub Date: 2024-10-12 DOI:10.1002/kjm2.12894
Xi-Mei Zhang, Ming-Jie Qing, Xin-Kuo Liu, Liang Peng
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摘要

本研究探讨了LNP023对狼疮性肾炎(LN)中AMPK/mTOR信号通路的影响及其对自噬和氧化应激的作用。建立了狼疮肾炎小鼠模型,并通过评估各种狼疮肾炎标志物(包括抗核抗体、ds-DNA、抗Sm抗体等)确认了肾损伤。小鼠接受了 LNP023、AMPK 激活剂 AICAR 或 AMPK 抑制剂多索吗啡的治疗。用 HE 和 Masson 染色法评估肾损伤和纤维化。免疫组化和 Western 印迹法评估了 AMPK、mTOR、LC3、Beclin1 和 p62 的表达水平。氧化应激和炎症标记物通过聚合酶链式反应和酶联免疫吸附试验进行测定。LN小鼠表现出低AMPK/p-AMPK和高mTOR/p-mTOR水平,同时伴有明显的肾损伤、纤维化、自噬功能降低和氧化应激升高。LNP023 治疗可改善这些参数,与 AICAR 合用时效果更佳。相反,多索吗啡则逆转了 LNP023 的治疗效果。补体因子 B 抑制剂 LNP023 通过介导 AMPK/mTOR 通路、促进自噬和减轻氧化应激促进 LN 小鼠的肾脏健康。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Complement factor B inhibitor LNP023 mediates the effect and mechanism of AMPK/mTOR on autophagy and oxidative stress in lupus nephritis.

This study investigated the impact of LNP023 on the AMPK/mTOR signaling pathway in lupus nephritis (LN) and its effects on autophagy and oxidative stress. A mouse model of LN was established, and renal injury was confirmed by assessing various LN markers, including antinuclear antibody, ds-DNA, anti-Sm antibody, and others. Mice were treated with LNP023, the AMPK activator AICAR, or the AMPK inhibitor dorsomorphin. Renal injury and fibrosis were evaluated using HE and Masson staining. Expression levels of AMPK, mTOR, LC3, Beclin1, and p62 were assessed by immunohistochemistry and Western blot. Oxidative stress and inflammatory markers were measured by polymerase chain reaction and enzyme-linked immunosorbent assay. LN mice exhibited low AMPK/p-AMPK and high mTOR/p-mTOR levels, alongside significant renal injury, fibrosis, reduced autophagy, and elevated oxidative stress. LNP023 treatment improved these parameters, with enhanced effects when combined with AICAR. Conversely, dorsomorphin reversed LNP023's therapeutic benefits. The complement factor B inhibitor LNP023 promotes kidney health in LN mice by mediating the AMPK/mTOR pathway, promoting autophagy, and attenuating oxidative stress.

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