RAGE抑制剂TTP488降低糖尿病性视网膜病变小鼠模型中的视网膜炎症的疗效

doi:10.3870/j.issn.1672-8009.2026.03.008

摘要/Abstract

摘要： 目的深入探索晚期糖基化终末产物受体抑制剂TTP488降低视网膜炎症的疗效及其作用机制。方法 30只雄性C57BL/6J小鼠随机分入3组(n=10):对照组、1型糖尿病(type I diabetes mellitus,T1DM)模型组和T1DM+TTP488组。建立链脲佐菌素(streptozotocin,STZ)诱导的T1DM小鼠模型。免疫荧光染色测定小鼠视网膜组织中小胶质细胞标记物(Iba1)阳性细胞活化程度;ELISA测定其中炎症因子TNF-α、IL-1β、IL-6的水平。体外细胞实验分组为细胞对照组、LPS组、LPS+TTP488组、LPS+shRNA-P65组和LPS+shRNA-NT组。采用脂多糖(lipopolysaccharide,LPS)诱导建立小鼠视网膜色素上皮原代细胞炎症模型。腺病毒载体介导敲低P65。RT-qPCR法测定细胞内VEGF-D mRNA的表达水平。蛋白质印迹法测定视网膜组织中和体外细胞内磷酸化NF-κB P65(p-P65)/P65和VEGF-D的表达水平。结果与T1DM模型组比较,T1DM+TTP488组小鼠视网膜组织中Iba1阳性细胞数量、细胞分支数和细胞分支连接点数(每视野个数)均减少(P<0.05);TNF-α、IL-1β、IL-6水平均降低(P<0.05);p-P65/P65和VEGF-D相对表达水平均降低(P<0.05)。与LPS组比较,LPS+TTP488组和LPS+shRNA-P65组VEGF-D mRNA相对表达水平均降低(P<0.05);p-P65和VEGF-D相对表达水平均下调(P<0.05)。结论 TTP488通过抑制NF-κB的活化下调VEGF-D的表达,可降低糖尿病性视网膜病变小鼠模型中的视网膜炎症和组织结构病变。

关键词: 糖尿病性视网膜病变, 炎症, 晚期糖基化终末产物, 晚期糖基化终末产物受体, TTP488, 血管内皮生长因子

Abstract: Objective To explore the efficacy and mechanisms of the receptor for advanced glycation end products inhibitor TTP488 in reducing retinal inflammation. Methods Thirty male C57BL/6J mice were randomly divided into 3 groups(n=10 each):control group,type I diabetes mellitus(T1DM) model group,and T1DM+TTP488 group.A T1DM mice model induced by streptozotocin(STZ)was established.Immunofluorescent staining targeting microglial cell markers(Iba1)was used to determine the activation degree of Iba1-positive cells in the retinal tissues of mice;and ELISA was used to measure the levels of inflammatory factors TNF-α,IL-1β and IL-6 in them.mRPE cells was divided into the following 5 groups for the further in vitro cell experiments:control group,LPS group,LPS+TTP488 group,LPS+shRNA-P65 group,LPS+shRNA-NT group.Lipopolysaccharide(LPS)was used to establish the primary mouse retinal pigment epithelial cells inflammatory model.Adenovirus vector was used to mediate the knockdown of P65.The expression level of VEGF-D mRNA in cells was determined by RT-qPCR.The expression levels of phosphorylated NF-κB P65(p-P65)/P65 and VEGF-D in the retinal tissues of mice as well as in in vitro cells were determined by Western blotting. Results Compared with those in the T1DM model group,the number of Iba1 positive cell branches and the number of Iba1 positive cell branch connection points(per field)in the T1DM+TTP488 group were decreased(P<0.05).The levels of TNF-α,IL-1β,and IL-6 were decreased(P<0.05).The relative expression levels of p-P65/P65 and VEGF-D were decreased(P<0.05).Compared with those in the LPS group,the relative expression level of VEGF-D mRNA in the LPS+TTP488 group and the LPS+shRNA-P65 group was decreased(P<0.05).The relative expression levels of p-P65 and VEGF-D were down-regulated(P<0.05). Conclusion TTP488 reduced the expression of VEGF-D by inhibiting the activation of NF-κB,thereby alleviating retinal inflammation and tissue structural abnormalities in the diabetic retinopathic mice model.

Key words: diabetic retinopathy, inflammation, advanced glycation end products, receptor for advanced glycation end products, TTP488, vascular endothelial growth factor

中图分类号:

王岚, 卢怡, 邹云春. RAGE抑制剂TTP488降低糖尿病性视网膜病变小鼠模型中的视网膜炎症的疗效[J]. 医学分子生物学杂志, 2026, 23(3): 294-301.

WANG Lan, LU Yi, ZOU Yunchun. Efficacy of RAGE Inhibitor TTP488 in Reducing Retinal Inflammation in Diabetic Retinopathy Mice Model[J]. Journal of Medical Molecular Biology, 2026, 23(3): 294-301.

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