梓醇对糖尿病小鼠视网膜病变的影响及作用机制

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摘要目的探讨梓醇对糖尿病小鼠视网膜病变的影响及其作用机制。方法选取雄性8周龄SPF级KK-Ay糖尿病小鼠28只，按随机数字表法分为模型组[100 mg/（kg·d）生理盐水]、氨基胍组[100 mg/（kg·d）氨基胍]、梓醇低剂量组[50 mg/（kg·d）梓醇]和梓醇高剂量组[100 mg/（kg·d）梓醇]，另选雄性8周龄SPF级C57BL/6J小鼠为空白组[100 mg/（kg·d）生理盐水]，每组各7只。五组均连续灌胃8周，并于干预前、干预4周后、干预8周后监测其血糖水平。给药8周后，HE染色观察视网膜病理改变，并对视网膜神经节细胞（RGC）计数；采用酶联免疫吸附试验检测五组血清白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、血管内皮生长因子（VEGF）、晚期糖基化终末产物（AGE）水平；Western blot测定视网膜血管内皮钙黏着蛋白（VE-cadherin）、晚期糖基化终末产物受体（RAGE）、磷酸化核因子-κB p65（P-NF-κB p65）蛋白表达。结果模型组干预8周后血糖水平高于干预前，梓醇低剂量组干预8周后血糖水平低于干预前，梓醇高剂量组干预4周后及干预8周后血糖水平均低于干预前，差异均有统计学意义（均P ＜ 0.05）。模型组干预前、干预4周后、干预8周后血糖水平均高于同一时间点的空白组，梓醇低剂量组干预8周后血糖水平低于同一时间点的模型组，梓醇高剂量组干预4周后、干预8周后血糖水平均低于同一时间点的模型组，差异均有统计学意义（均P ＜ 0.05）。空白组视网膜表面光滑平整，结构清晰完整；模型组视网膜结构疏松、厚度变薄，视网膜细胞排列无序；梓醇低剂量组视网膜结构疏松、厚度较薄；梓醇高剂量组视网膜结构、细胞排列及视网膜厚度较模型组有所改善。干预8周后，模型组RGC数量少于空白组；梓醇高剂量组RGC数量多于模型组，差异有高度统计学意义（P ＜ 0.01）。模型组IL-1β、TNF-α、VEGF、AGE水平均高于空白组，梓醇低、高剂量组IL-1β、TNF-α、VEGF、AGE水平均低于模型组，差异均有统计学意义（P ＜ 0.05或P ＜ 0.01）。模型组VE-cadherin表达低于空白组，RAGE、P-NF-κB p65蛋白表达高于空白组，差异均有统计学意义（均P ＜ 0.05）。梓醇低、高剂量组VE-cadherin表达高于模型组，RAGE、P-NF-κB p65蛋白表达低于模型组，差异均有高度统计学意义（均P ＜ 0.01）。结论梓醇可降低糖尿病小鼠血糖和血清炎症因子水平，改善糖尿病小鼠视网膜病变，其作用机制可能与抑制AGE/ RAGE/NF-κB信号通路有关。

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	吴震杜秋

关键词 ：梓醇, 糖尿病视网膜病变, 晚期糖基化终末产物, 晚期糖基化终末产物受体, 磷酸化核因子-&kappa, B

Abstract：Objective To study the effects and mechanism of catalpol on retinopathy in mice with diabetes mellitus. Methods A total of 28 SPF KK-Ay diabetic mice aged eight weeks were selected. According to random number table method, they were divided into model group [100 mg/(kg·d) normal saline], Aminoguanidine group [100 mg/(kg·d) Aminoguanidine], catalpol low-dose group [50 mg/(kg·d) catalpol] and catalpol high-dose group [100 mg/(kg·d) catalpol]. SPF C57BL/6J male mice aged eight weeks were selected as blank group [100 mg/(kg·d) normal saline], with seven mice in each group. All the five groups were given intragastric gavage for eight weeks continuously, and their blood glucose levels were monitored before, four and eight weeks after intervention. Eight weeks after administration, pathological changes of retina were observed by HE staining and retinal ganglion cells (RGC) were counted. Serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and advanced glycation end product (AGE) in five groups were determined by enzym-linked immunosorbent assay. The expression levels of vascular endothelial cadherin (VE-cadherin), advanced glycolylation end product receptor (RAGE) and phosphorylated nuclear factor-κB p65 (P-NF-κB p65) in retinal cells were determined by Western blot. Results After eight weeks of intervention, the blood glucose levels in the model group was higher than those before interlention, the blood glucose level in the catalpol low-dose group was lower than before, the blood glucose level in the catalpol high-dose group was lower than before and after four weeks and eight weeks of intervention, the differences were statistically significant (all P ＜ 0.05). The blood glucose levels in the model group before intervention, four weeks after intervention and eight weeks intervention were higher than those at the same time points of the blank group， the blood glucose levels in the catalpol low-dose group after eight weeks of intervention were lower than those at the same time point in the model group, the blood glucose levels of catalpol high-dose group after four weeks and eight weeks of intervention were lower than those in the model group at the same time points, with all statistical significance (all P ＜ 0.05). The retinal surface of blank group was smooth, and the structure was clear and complete. In the model group, the retinal structure was loose and the retinal cells were disordered. The retinal structure of catalpol low-dose group was loose and thin. The retinal structure, cell arrangement and retinal thickness were improved in catalpol high-dose group compared with model group. After eight weeks of intervention, the number of RGC in the model group was less than that in the blank group, the number of RGC in catalpol high-dose group was higher than that in model group, and the differences were highly statistically significant (P ＜ 0.01). The levels of IL-1β, TNF-α, VEGF, and AGE in model group were higher than those in blank group, and the levels of IL-1β, TNF-α, VEGF, and AGE in catalpol low-dose and high-dose groups were lower than those in model group, with statistical significance (P ＜ 0.05 or P ＜ 0.01). The expression of VE-cadherin in model group was lower than that in blank group, and the expression of RAGE and P-NF-κB p65 in model group was higher than that in blank group, with statistical significance (all P ＜ 0.05). The expression of VE-cadherin in catalpol low-dose and high-dose groups was higher than that in model group, and the expression of RAGE and P-NF-κB p65 protein in catalpol low-dose and high-dose groups was lower than that in model group, with highly statistical significance (P ＜ 0.01). Conclusion Catalpol can reduce blood glucose and serum inflammatory factor levels, thereby improving retinopathy in mice with diabetes mellitus, and its mechanism may be related to the inhibition of AGE/RAGE/NF-κB signaling pathway.

Key words： Catalpol Diabetic retinopathy Advanced glycation end product Advanced glycolylation end product receptor Phosphorylated nuclear factor-κB p65

基金资助:

江苏省研究生科研与实践创新计划项目（KYCX19_1271）；
江苏省南京市卫生科技发展专项资金项目（YKK18132）；
江苏省南京市中医药青年人才培养计划项目（ZYQ20012）。

通讯作者: 杜秋（1984-），女，博士，副主任药师；研究方向：内分泌药理。

引用本文:

吴震杜秋. 梓醇对糖尿病小鼠视网膜病变的影响及作用机制[J]. 中国医药导报, 2021, 18(19): 17-21.
WU Zhen DU Qiu. Effects and mechanism of catalpol on retinopathy in mice with diabetes mellitus. 中国医药导报, 2021, 18(19): 17-21.

链接本文:

https://www.yiyaodaobao.com.cn/CN/ 或 https://www.yiyaodaobao.com.cn/CN/Y2021/V18/I19/17

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