芪蛭降糖胶囊调控NLRP3/caspase-1/GSDMD通路抑制足细胞焦亡改善糖尿病肾损伤的机制研究  

Mechanism of Qizhi Jiangtang capsule inhibits podocyte pyroptosis to improve kidney injury in diabetes nephropathy by regulating NLRP3/caspase-1/GSDMD pathway

作　　者：苏珊珊[1] 郭兆安[1] 杨欢 刘慧[1] 唐静楠 姜晓宇 SU Shanshan;GUO Zhaoan;YANG Huan;LIU Hui;TANG Jingnan;JIANG Xiaoyu(Department of Nephrology,Shandong Provincial Hospital of Traditional Chinese Medicine,Jinan 250011,China)

机构地区：[1]山东省中医院肾病科,山东济南250011

出　　处：《细胞与分子免疫学杂志》2025年第3期204-210,共7页Chinese Journal of Cellular and Molecular Immunology

基　　金：山东省自然科学基金中医药联合基金项目(ZR2022LZY005)。

摘　　要：目的 探究芪蛭降糖胶囊(QZJT)通过含pyrin结构域NOD样受体家族3/半胱天冬酶1/消皮素D(NLRP3/caspase-1/GSDMD)信号通路对糖尿病肾病(DN)小鼠肾损伤的影响。方法 小鼠随机分为6组,分别为正常组(NC)、模型组(DN)、 QZJT低剂量组(L-QZJT)、 QZJT高剂量组(H-QZJT)、阳性对照组(参芪降糖颗粒给药,SQJT)、 ML385组[核呼吸因子2(Nrf2)抑制剂],模型构建成功后给药处理,通过测定空腹血糖(FBG)、 24 h尿白蛋白(UAlb)、血清肌酐(SCr)、血尿素(BUN)及肾脏/体质量比值(K/B)评估小鼠肾功能损伤程度;HE及PAS染色评估肾组织的病理变化;ELISA检测血清中炎性细胞因子白细胞介素1β(IL-1β)、 IL-18含量;Western blot法检测足细胞标志物及相关通路蛋白水平。结果 与NC组相比,DN组的FBG、 24 h UAlb、 SCr和BUN升高,K/B质量比值升高。与DN组相比,QZJT低剂量及高剂量给药组的FBG、 24 h UAlb、 SCr及BUN均降低,同时K/B质量比降低,高剂量QZJT的治疗效果与参芪降糖颗粒相当。QZJT改善DN小鼠肾组织病理学损伤,提高了足细胞标志物肾病蛋白(Nephrin)的蛋白水平,降低了NLRP3、凋亡相关斑点样蛋白(ASC)、 pro-caspase-1和GSDMD-N的蛋白水平。ML385处理后,小鼠的肾组织细胞肿胀和形态改变,炎性浸润面积增加,NLRP3、 ASC、 pro-caspase-1和GSDMD-N的蛋白水平上调,IL-1β和IL-18水平升高。结论 QZJT可能通过作用Nrf2调控NLRP3/caspase-1/GSDMD通路抑制足细胞焦亡,改善DN小鼠肾损伤。Objective To investigate the impact of Qizhi Jiangtang Capsule(QZJT)on renal damage in diabetic nephropathy(DN)mice via NOD like receptors family pyrin domain containing 3/caspase-1/Gasdermin D(NLRP3/caspase-1/GSDMD)signaling pathway.Methods Mice were randomly allocated into six experimental groups:a normal control group(NC),a diabetic nephropathy model group(DN),a low-dose QZJT treatment group(L-QZJT),a high-dose QZJT treatment group(H-QZJT),a positive control group administered Shenqi Jiangtang Granules(SQJT),and an ML385 group(treated with an inhibitor of nuclear factor erythroid 2-related factor 2,Nrf2).Upon successful model induction,therapeutic interventions were commenced.Renal function impairment in the mice was evaluated through quantification of fasting blood glucose(FBG),24-hour urinary albumin(UAlb),serum creatinine(SCr),blood urea nitrogen(BUN),and the kidney-to-body mass ratio(K/B).Renal tissue pathology was evaluated using HE and PAS staining.Serum levels of inflammatory cytokines IL-1βand IL-18 were quantified by ELISA.Levels of podocyte markers and proteins involved in relevant pathways were assessed using Western blot analysis.Results Compared with the NC group,FBG,24 h UAlb,SCr,and BUN were increased in the DN group,and the K/B mass ratio was also increased.In contrast,compared with the DN group,FBG,24 h UAlb,SCr,and BUN in both the low-dose(L-QZJT)and high-dose Quanzhou Jintang(H-QZJT) groups were decreased, and the K/B mass ratio was decreased as well. The therapeutic efficacy of H-QZJT was comparable to that of Shenqi Jiangtang Granules. QZJT ameliorated renal histopathological injury in DN mouse, increased the protein levels of Nephrin (a podocyte marker), and decreased the protein levels of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), pro-caspase-1, and GSDMD-N. After ML385 treatment, renal cells exhibited swelling and morphological changes, the inflammatory infiltrate area was enlarged, the protein levels of NLRP3, ASC, pro-caspase-1, and GSDMD-N were up-regulate

关 键 词：芪蛭降糖胶囊(QZJT) 糖尿病肾病 NLRP3/caspase-1/GSDMD信号通路 NRF2 细胞焦亡 

分 类 号：R392[医药卫生—免疫学] R587.2[医药卫生—基础医学] R692.6