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    基于NLRP3/GSDMD信号通路探索大黄素对糖尿病肾病大鼠肾组织的修复作用

    Renoprotective Effects of Emodin in Diabetic Kidney Disease Rats via the NLRP3/GSDMD Signaling Pathway

      摘要
    • 摘要:
      目的 基于NLRP3/GSDMD信号通路探索大黄素对链脲佐菌素(streptozotocin，STZ)诱导大鼠糖尿病肾病(diabetic kidney disease，DKD)模型焦亡的影响。
      方法 单侧肾切除联合单次腹腔注射STZ诱导动物DKD模型，分为对照组，模型组，大黄素40、80 mg·kg−1组及NLRP3抑制剂组(MCC950，10 mg·kg−1)。检测各组治疗前后肾功能指标并动态记录体质量及血糖值变化；过碘酸-希夫染色(periodic acid-Schiff stain，PAS)和Masson染色观察动物肾脏受损及修复情况；RT-qPCR检测IL-18、IL-1β、HO-1及NPHS2基因的表达水平变化；Western blotting检测Nephrin、NPHS2、CD2AP、NLRP3、GSDMD及Caspase-1蛋白表达量变化。
      结果 经大黄素干预的DKD大鼠各项肾功能指标均得到改善；与模型组相比，80 mg·kg−1的大黄素干预显著降低了血清肌酐、血尿素氮等各项肾功能指标；Nephrin、NPHS2、CD2AP等蛋白含量显著上调(P<0.05或P<0.01)，NLRP3、GSDMD、Caspase-1蛋白表达含量均显著下调(P<0.05或P<0.01)；IL-18、IL-1β等炎症因子含量显著下降(P<0.01或P<0.001)，并且NPHS2及HO-1含量也出现不同程度的上升(P<0.05或P<0.01)。
      结论 大黄素通过调节NLRP3/GSDMD焦亡信号通路，改善了DKD大鼠的肾功能及病理损伤。

       

      Abstract:
      OBJECTIVE To investigate the effect of emodin on pyroptosis in rat model of diabetic kidney disease(DKD) induced by streptozotocin(STZ), based on the NLRP3/GSDMD signaling pathway.
      METHODS The DKD rat model was established via unilateral nephrectomy combined with a single intraperitoneal injection of STZ. Animals were allocated into five groups: control group, model group, emodin 40, 80 mg·kg−1), and NLRP3 inhibitor group(MCC950, 10 mg·kg−1). Renal function parameters were measured before and after treatment. Body weight and blood glucose levels were monitored. Kidney histopathology was evaluated using periodic acid–Schiff(PAS) staining and Masson's trichrome staining to assess renal structural damage and recovery. The mRNA expression of IL-18, IL-1β, HO-1, and NPHS2 was quantified by RT-qPCR. Protein levels of Nephrin, NPHS2, CD2AP, NLRP3, GSDMD, and Caspase-1 were determined by Western blotting.
      RESULTS Emodin intervention improved various renal function indicators in DKD rats. Compared with the model group, 80 mg·kg−1 emodin significantly reduced serum creatinine and blood urea nitrogen levels Protein levels of Nephrin, NPHS2, and CD2AP were significantly up-regulated(P<0.05 or P<0.01), while the expression of NLRP3, GSDMD, and Caspase-1 was significantly down-regulated(P<0.05 or P<0.01). Inflammatory factors such as IL-18 and IL-1β decreased(P<0.01 or P<0.001), and the expression of NPHS2 and HO-1 increased to varying degrees(P<0.05 or P<0.01).
      CONCLUSION Emodin improves renal function and pathological damage in DKD rats by regulating the NLRP3/GSDMD-mediated pyroptosis signaling pathway.

       

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