J Inflamm Res:苏茵解毒方通过下调MAVS/NLRP3抑制焦亡和上皮-间质T转移减轻肾损伤

2021-12-18 Vivi MedSci原创

蛋白尿是慢性肾脏疾病(CKD)的独立危险因素,通过激活NLRP3炎症小体,白蛋白诱导的小管间质炎症和上皮-间质转化(EMT)是CKD的一个潜在治疗靶点。探究苏茵解毒方对CKD的治疗作用及其机制。

背景:蛋白尿慢性肾脏疾病(CKD)的独立危险因素,通过激活NLRP3炎症小体,白蛋白诱导的小管间质炎症和上皮-间质转化(EMT)是CKD的一个潜在治疗靶点苏茵解毒方出自《不知医必要》卷一,现代研究发现其可改善蛋白尿,延缓肾功能衰竭,但其肾保护机制仍不清楚。

目的:采用腺嘌呤致大鼠肾衰竭模型,探讨SDP对尿蛋白、肾功能和炎症指标的影响。体外实验中,采用人肾小管上皮HK-2细胞模拟蛋白尿对肾小管的破坏,探讨SDP对线粒体功能障碍导致MAVS激活NLRP3的影响,研究HK-2细胞对焦变和EMT的诱导作用。

方法:首先,用腺嘌呤灌胃建立大鼠肾衰竭模型(腺嘌呤2.5%,200 mg/kg/d,每天灌胃,持续4周),评估肾功能、蛋白尿、血清炎症指标及肾脏病理,低、高浓度SDG干预后进行NLRP3炎症小体肾免疫组化染色。其次,用白蛋白体外建立肾小管上皮HK-2细胞模型,将苏茵解毒方冻干粉(SDP)和选择性直接NLRP3抑制剂CY-09与白蛋白共孵育后,检测NLRP3炎症小体信号通路蛋白表达。在体外进一步测定ATP、SOD、线粒体膜电位和ROS,观察SDP干预后线粒体功能的变化。用siRNA敲除线粒体抗病毒信号蛋白(MAVS),并用Western blotting、PCR和免疫荧光技术验证MAVS与NLRP3的相互作用。

结果:肾免疫组化结果显示腺嘌呤组纤维化标记物I和纤维连接蛋白水平显著升高,SDG低、高剂量组纤维连接蛋白水平降低。肾皮质HE染色显示,与对照组相比,腺嘌呤组肾间质大部分出现炎症,肾小管数量减少,肾结构萎缩消失,肾间质淋巴细胞浸润增多,病灶周围一些肾小管的腔变大,上皮细胞水肿。Masson染色组织表现为高皮质损伤,损伤部位及周围肾小管-间质胶原纤维增生较多,呈深蓝色。PAS染色观察到肾小球系膜基质无明显增加,基底膜无明显增厚;而髓质中少量肾小管均为PAS阳性,且SDG低、高剂量组这些病灶均得到改善。这些结果表明SDG减轻了腺嘌呤诱导的肾组织纤维化

模型组大鼠血尿素氮、血清肌酐、血清胱抑素和血尿酸升高,尿白蛋白排泄率和血清白蛋白排泄率降低。SDG低、高剂量组肾功能指标改善,低蛋白血症改善,尿蛋白排泄减少。与对照组相比,模型组的血清炎症标志物IL-1、IL-1β、IL-18和MCP-1显著增加,SDG低、高剂量组的炎症反应改善。腺嘌呤增加肾组织中NLRP3、caspase-1、GSDMD和IL-1β的水平,低剂量和高剂量SDG均降低其水平。这些数据表明,SDG改善腺嘌呤诱导的肾功能障碍、蛋白尿、低蛋白血症,降低血清炎症和肾内NLRP3炎症小体成分的表达

在体外,SDP和CY-09增强白蛋白损伤后的细胞活力,抑制NLRP3炎症信号通路诱导的细胞焦亡和参与EMT的蛋白表达。进一步实验发现,SDP能缓解白蛋白引起的线粒体功能障碍。MAVS的敲除降低了NLRP3通路蛋白及其mRNA的表达水平,同时也削弱了NLRP3的共定位,从而减少了细胞的焦亡。

结论:SDP通过调节白蛋白诱导的线粒体功能障碍/MAVS/NLRP3-ASC-caspase-1炎症小体信号通路保护肾小管上皮细胞的细胞焦亡和EMT。这为苏茵解毒方的临床推广应用提供了理论基础。

文献来源:

Zhu, Y., Huang, G., Yang, Y., et al. (2021). Chinese Herbal Medicine Suyin Detoxification Granule Inhibits Pyroptosis and Epithelial-Mesenchymal Transition by Downregulating MAVS/NLRP3 to Alleviate Renal Injury. Journal of inflammation research, 14, 6601–6618. https://doi.org/10.2147/JIR.S341598

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    2022-02-13 lxg951
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    2021-12-20 yuandd
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    2021-12-20 xiaoyeshuang
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    2021-12-20 vera_1207

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