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| 积雪草苷调节NLRP3/Caspase-1/GSDMD信号通路减轻慢性低氧大鼠肾损伤 |
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段争1,2, 杨丹宁1,2, 曹瑞琪1,2, 聂亚珍1,2, 陈成1,2, 刘伟丽2, 陈照立2
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1.天津中医药大学研究生院, 天津 301617;2.军事科学院军事医学研究院, 天津 300050
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| 摘要: |
| [目的] 探究积雪草苷（AS）对慢性高原低压低氧大鼠肾脏损伤的保护机制。[方法] 采用高原低压低氧环境动物模拟试验舱（氧分压约11.0 kPa，23 h/d）模拟海拔6 000 m高原环境，将32只Wistar大鼠随机分为常压常氧对照组（Normoxia）、高原低压低氧模型组（HH）、积雪草苷低剂量干预组（HH+40AS，40 mg/kg）和高剂量干预组（HH+80AS，80 mg/kg），每组8只。实验结束后，测定大鼠24 h尿液指标、血清肌酐（Scr）、尿素氮（BUN）水平；苏木精-伊红（HE）染色法、Masson三色染色法、高碘酸-希夫（PAS）染色法观察肾脏组织病理学变化；TUNEL染色检测肾脏组织细胞死亡；超氧化物歧化酶（SOD）、丙二醛（MDA）、乳酸脱氢酶（LDH）试剂盒检测血清及肾组织氧化应激水平；酶联免疫吸附试验（ELISA）法检测血清及肾组织炎症因子[白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）]含量；蛋白免疫印记（Western blot）法检测肾组织中NOD样受体热蛋白结构域相关蛋白3（NLRP3）、凋亡相关斑点样蛋白（ASC）、Caspase-1、Caspase-1-p20、消皮素D（GSDMD）及其N端片段（GSDMD-N）的蛋白表达水平。[结果] 与Normoxia组相比，HH组肾组织呈明显病理损伤症状，24 h尿液指标、Scr、BUN显著升高，TUNEL阳性细胞数增多，肾组织及血清中的MDA、LDH、IL-1β、IL-18水平上调，且NLRP3、ASC、Caspase-1-p20、GSDMD-N蛋白表达均显著增加（P<0.01），肾组织及血清中的SOD水平显著下降（P<0.01）。AS干预后，尤其是HH+80AS组，能明显改善肾功能指标，减轻肾脏组织病理损伤和细胞死亡，降低炎症因子水平，并剂量依赖性地抑制NLRP3炎症小体活化及下游GSDMD的剪切。[结论] AS可通过抑制NLRP3/Caspase-1/GSDMD信号通路的激活，减轻大鼠肾脏组织的焦亡及氧化应激反应，从而减轻其慢性高原低压低氧肾组织损伤及纤维化。 |
| 关键词: 积雪草苷 高原低压低氧 肾脏损伤 NLRP3 焦亡 |
| DOI：10.11656/j.issn.1673-9043.2026.08.06 |
| 分类号:R285.5 |
| 基金项目: |
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| Asiaticoside alleviates renal injury in chronically hypoxic rats by modulating the NLRP3/Caspase-1/GSDMD signaling pathway |
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DUAN Zheng1,2, YANG Danning1,2, CAO Ruiqi1,2, NIE Yazhen1,2, CHEN Cheng1,2, LIU Weili2, CHEN Zhaoli2
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1.Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China;2.Academy of Military Medicine, Academy of Military Sciences, Tianjin 300050, China
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| Abstract: |
| [Objective] To investigate the protective mechanism of asiaticoside（AS）against renal injury in rats exposed to chronic hypobaric hypoxia. [Methods] A simulated high altitude environment（approximately 6 000 meters，with a partial pressure of oxygen of about 11.0 kPa for 23 h/d）was created using an animal hypobaric hypoxia chamber. Thirty-two Wistar rats were randomly divided into four groups（n=8 each）：a normoxic control group（Normoxia），a hypobaric hypoxia model group（HH），a low-dose asiaticoside intervention group（HH+40AS， 40 mg/kg），and a high dose asiaticoside intervention group（HH + 80AS，80 mg/kg）. After the experiment，the following assessments were performed：24 hour urinary indices，serum creatinine（Scr），and blood urea nitrogen （BUN）levels；renal histopathological changes observed via hematoxylin-eosin（HE）staining，Masson’s trichrome staining，and periodic acid Schiff（PAS）staining；renal cell death detected by TUNEL staining；oxidative stress levels in serum and renal tissue measured using kits for superoxide dismutase（SOD），malondialdehyde（MDA），and lactate dehydrogenase（LDH）；serum and renal tissue levels of inflammatory factors [interleukin 1β（IL 1β）， interleukin-18（IL-18）] measured by enzyme-linked immunosorbent assay（ELISA）；and protein expression levels of NOD-like receptor thermal protein domain-associated protein 3（NLRP3），apoptosis-associated speck-like protein containing a CARD（ASC），Caspase 1，cleaved Caspase 1（p20），gasdermin D（GSDMD），and its N terminal fragment（GSDMD-N）in renal tissue determined by Western blot. [Results] Compared with the Normoxia group， the HH group showed significant renal histopathological damage，increased 24-hour urinary indices，Scr，and BUN， a higher number of TUNEL-positive cells，upregulated levels of MDA，LDH，IL-1β，and IL-18 in both renal tissue and serum，significantly increased protein expression of NLRP3，ASC，cleaved Caspase-1（p20），and GSDMD-N（P< 0.01），and significantly decreased SOD levels in renal tissue and serum（P<0.01）. Asiaticoside intervention， especially in the HH+80AS group，markedly improved renal function indicators，alleviated renal histopathological damage and cell death，reduced inflammatory factor levels，and dose dependently inhibited the activation of the NLRP3 inflammasome and the cleavage of downstream GSDMD. [Conclusion] Asiaticoside can alleviate pyroptosis and oxidative stress in rat renal tissue by inhibiting the activation of the NLRP3/Caspase 1/GSDMD signaling pathway，thereby mitigating renal tissue injury and fibrosis induced by chronic hypobaric hypoxia. |
| Key words: asiaticoside hypobaric hypoxia kidney injury NLRP3 pyroptosis |
