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    基于Wnt/β-catenin通路探讨大黄糖络丸对糖尿病肾病db/db小鼠肾纤维化的作用机制

    Mechanism of Dahuang Tangluo Pills on Renal Fibrosis in db/db Mice with Diabetic Nephropathy Based on Wnt/β-catenin Pathway

      摘要
    • 摘要:
      目的 观察大黄糖络丸对糖尿病肾病db/db小鼠肾功能及纤维化的影响，并基于Wnt/β-catenin通路探讨其可能的作用机制。
      方法 将40只db/db小鼠随机分为模型组、达格列净组(1.5 mg·kg−1)和大黄糖络丸低、中、高剂量组(0.9、1.8、3.6 g·kg−1)，每组8只。另取8只db/m小鼠为正常对照组。正常对照组和模型组给予等体积蒸馏水，6 组小鼠每日灌胃1次，连续10周。定期测量小鼠空腹血糖(fasting blood glucose，FBG)，收集尿液并检测尿微量白蛋白、尿肌酐、尿微量白蛋白/肌酐比值(albumin-to-creatinine ratio，ACR)；眼球取血，用全自动生化分析仪检测小鼠胆固醇(cholesterol，CHO)、甘油三酯(triglyceride，TG)。Masson染色观察肾脏组织纤维化程度；Real-time PCR、Western blotting 检测肾组织中 Wnt3a、β-catenin、GSK-3β及p-GSK-3β的mRNA及蛋白表达水平。透射电子显微镜观察肾脏细胞超微结构的改变，并观测小鼠肾脏的病理损伤程度。采用SPSS 26.0统计软件进行数据分析。
      结果 与正常对照组相比，模型组小鼠一般状态较差，小鼠肾脏出现明显损伤及纤维化，FBG、CHO、TG、ACR水平均显著升高(P<0.01)，肾脏组织中Wnt3a、β-catenin、GSK-3β、p-GSK-3β mRNA及蛋白表达水平均明显提高(P<0.01)。与模型组相比，各给药组小鼠一般状态、肾组织超微结构损伤有不同程度改善，肾纤维化程度和FBG、CHO、TG、ACR水平有不同程度降低，肾组织Wnt3a、β-catenin、 GSK-3β及 p-GSK-3β的mRNA和蛋白表达水平有不同程度降低，且大黄糖络丸高剂量组作用最明显(P<0.01)，大黄糖络丸对糖尿病肾病db/db小鼠作用呈剂量依赖性。
      结论 大黄糖络丸可有效降低血糖，改善肾纤维化，其机制可能与抑制 Wnt/β-catenin通路有关。

       

      Abstract:
      OBJECTIVE To observe the effects of Dahuang Tangluo pills on renal function and fibrosis in db/db mice with diabetic nephropathy, and to explore the possible mechanism based on Wnt/β-catenin pathway.
      METHODS  Forty db/db mice were randomly divided into model group, dagliprazin group(1.5 mg·kg−1), and low, medium, high dose groups(0.9, 1.8, 3.6 g·kg−1) of Dahuang Tangluo pills with 8 mice in each group. Another 8 db/m mice were selected as normal group. Normal group and model group were given equal volume normal saline, and 6 groups were given intragastric administration once a day for 10 weeks. Fasting blood glucose(FBG) was measured regularly, urine was collected and microalbumin, urinary creatinine and microalbumin-to-creatinine ratio(ACR) were detected. Cholesterol(CHO) and triglyceride(TG) were detected by automatic biochemical analyzer. The degree of renal fibrosis was observed by Masson staining. Real-Time PCR and Western blotting were used to detect the mRNA and protein expression level of Wnt3a, β-catenin, GSK-3β and p-GSK-3β in kidney. The ultrastructure of kidney cells was observed by transmission electron microscope, and the pathological injury degree of mouse kidney was observed. SPSS 26.0 statistical software was used for data analysis.
      RESULTS Compared with normal group, the kidney in model group showed obvious damage and fibrosis, the contents of FBG, CHO, TG and ACR were significantly increased(P<0.01), and the mRNA and protein expression levels of Wnt3a, β-catenin, GSK-3β and p-GSK-3β in kidney tissues were significantly increased(P<0.01). Compared with the model group, the general state and renal tissue ultrastructure damage of mice in each treatment group were improved to varying degrees. The degree of renal fibrosis, FBG, CHO, TG, and ACR were reduced. The mRNA and protein expression levels of Wnt3a, β-catenin, GSK-3β, and p-GSK-3β in renal tissue were also reduced. The high-dose group of Dahuang Tangluo pills had the most significant effect(P<0.01). Effect of Dahuang Tangluo pills on db/db mice with diabetic nephropathy showed a dose-dependent relationship.
      CONCLUSION Dahuang Tangluo pills can effectively reduce blood glucose and improve renal fibrosis, the mechanism of which may be related to the inhibition of Wnt/β-catenin pathway.

       

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