马兜铃酸I通过激活甘露聚糖结合凝集素丝氨酸蛋白酶1-补体系统促进肾小管间质纤维化

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2025-08-21 DOI:10.1016/j.fct.2025.115708

Chen Wang , Hong Zhang , Jiahe Wang , Huimin Wu , Jing Ye , Qi Zhang , Baoping Jiang , Langqun Chen , Ying Wang , Siyu Cheng , Jiahui Ying , Yujie Xiang , Yiran Cheng , Liang Zhang

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引用次数: 0

摘要

马兜铃酸I （AAI）激活补体系统，引发炎症和肾间质纤维化（RIF）。本研究探讨甘露聚糖结合凝集素丝氨酸蛋白酶1 （MASP1）在aai诱导的RIF中的作用。用AAI（2.5、5、10 μM）处理人近端小管（HK-2）细胞可增加炎症因子、纤维化蛋白、补体因子C3a和MASP1/MASP2的表达。aai处理（5 mg/kg） C57BL/6J小鼠也出现类似的升高。在HK-2细胞中使用siRNA （siMASP1）或抑制剂（C1INH, 100 μg/mL）抑制MASP1可降低aai诱导的C3a升高、补体激活、炎症、MASP2和纤维化蛋白。相应地，使用腺相关病毒9 （AAV9-siMASP1）在小鼠肾中原位抑制MASP1可抑制AAI暴露后补体激活、肾脏炎症和RIF。这些结果表明，AAI通过激活masp1 -补体通路促进RIF，导致C3a释放和炎症。本研究阐明了AAI诱导RIF的机制，并提示抑制MASP1可作为抗AAI毒性的潜在治疗策略。

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Aristolochic acid I promotes renal tubulointerstitial fibrosis by activating the mannan-binding lectin serine protease 1-complement system

Aristolochic acid I (AAI) activates the complement system, triggering inflammation and renal interstitial fibrosis (RIF). This study investigated the role of mannan-binding lectin serine protease 1 (MASP1) in AAI-induced RIF. Treating human proximal tubular (HK-2) cells with AAI (2.5, 5, 10 μM) increased inflammatory factors, fibrosis proteins, complement factor C3a, and MASP1/MASP2 expression. Similar increases occurred in AAI-treated (5 mg/kg) C57BL/6J mice. Inhibiting MASP1 using siRNA (siMASP1) or an inhibitor (C1INH, 100 μg/mL) in HK-2 cells reduced AAI-induced C3a elevation, complement activation, inflammation, MASP2, and fibrosis proteins. Correspondingly, in situ renal inhibition of MASP1 in mice using adeno-associated virus 9 (AAV9-siMASP1) suppressed complement activation, kidney inflammation, and RIF following AAI exposure. These results demonstrate that AAI promotes RIF by activating the MASP1-complement pathway, leading to C3a release and inflammation. This study elucidates a mechanism for AAI-induced RIF and suggests MASP1 inhibition as a potential therapeutic strategy against AAI toxicity.

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.