α-硫辛酸抑制炎症信号TLR4和NLRP3的活化在糖尿病大鼠肾组织纤维化中的保护作用  

Alpha lipoic acid provides protection on renal tissue fibrosis of diabetic rats by inhibiting activation of TLR4 and NLRP3 inflammatory signal

作　　者：肖瑛 袁质平[3] 彭灿 张小欢 张莹莹 王圆圆[1,2] 石明隽 张帆[1,2] 孙兰 郭兵[1,2] XIAO Ying;YUAN Zhi-ping;PENG Can;ZHANG Xiao-huan;ZHANG Ying-ying;WANG Yuan-yuan;SHI Ming-jun;ZHANG Fan;SUN Lan;GUO Bing(Dept of Pathophysiology,Guizhou Medical University,Guiyang550025,China;Guizhou Provincial Key Lab of Pathogenesis & Drug Research on Common Chronic Diseases,Guizhou Medical University,Guiyang550025,China;Dept of Otolaryngology,City Hospital,Guizhou Medical University,Guiyang550025,China)

机构地区：[1]贵州医科大学基础医学院病理生理学教研室,贵州贵阳550025 [2]贵州医科大学贵州省常见慢性疾病发病机制及药物研究重点实验室,贵州贵阳550025 [3]贵州医科大学大学城医院五官科,贵州贵阳550025

出　　处：《中国药理学通报》2019年第3期335-340,共6页Chinese Pharmacological Bulletin

基　　金：贵州省科技厅联合基金资助项目(黔科合LH字[2016]7355);贵州省教育厅青年科技人才成长资助项目(黔教合KY字[2017]165);贵阳市科技局基金资助项目(筑科合同[20161001]42号)

摘　　要：目的观察α-硫辛酸(ALA)对糖尿病(DM)大鼠肾组织Notch2、TLR4、NLRP3及炎性因子表达的影响,探讨ALA在糖尿病肾病(DN)中抗炎、抗纤维化的可能保护机制。方法 STZ复制DM模型,分为DM组和ALA组,同时设对照组。8周后处死大鼠,测定生化指标和氧化应激水平,免疫组化观察肾皮质Notch2、TLR4、NLRP3的表达部位,Western blot检测肾组织中Notch2、TLR4、NLRP3和Col-Ⅳ蛋白的表达,ELISA检测肾组织炎性因子IL-6和TNF-α的含量。结果与对照组相比,DM组大鼠血糖、24 h尿蛋白、总胆固醇和甘油三酯升高,T-AOC水平降低,MDA增多;ALA组除了血糖外,其余生化指标均低于DM组,而T-AOC活性增高,MDA含量降低。DM组肾组织Notch2、TLR4、NLRP3、Col-Ⅳ蛋白表达增多,炎性因子增多,ALA组各指标均降低。结论 ALA可下调DM大鼠肾组织TLR4和NLRP3炎症信号,减少炎性因子的表达和细胞外基质的沉积,从而减轻DN炎症反应和纤维化病变的发生发展,其机制可能与抑制Notch2蛋白的表达有关。Aim To investigate the effects of alpha lipoic acid(ALA)on Notch2,TLR4,NLRP3 and inflammatory factor expression in renal tissues of diabetes mellitus(DM)rats,and to explore its possible mechanism of anti-inflammatory and anti-fibrosis by Alpha lipoic acid.Methods The diabetic rat model was established by streptozotocin.The rats were divided into two groups:the DM group and ALA group.Meanwhile,and another eight rats were used as normal control(NC group).After eight weeks,the rats were sacrificed to detect the relevant biochemical parameters and oxidative stress indexes.In addition,immunohistochemical staining was employed to detect the protein expression localization sites of Notch2,TLR4 and NLRP3.Western blot analysis was used to detect the expression of Notch2,TLR4,NLRP3 and collagenⅣproteins in renal tissues.ELISA was utilized to detect the inflammatory factor expression of IL-6 and TNF-α.Results Compared with NC group,the levels of blood glucose,24h urine protein,total cholesterol and triglyceride all increased in DM group,and the activity of T-AOC was reduced whereas MDA content was up-regulated in DM group,all items but blood glucose were significantly reduced in ALA group,and the activity of T-AOC remarkably increased,while MDA content was reduced in ALA group.Compared with NC group,the protein levels of Notch2,TLR4,NLRP3 and collagenⅣin kidneys were raised,and the inflammatory factor expression of IL-6 and TNF-αsignificantly increased in DM group.Conclusions ALA may down-regulate the inflammatory signal of TLR4 and NLRP3 in kidney of diabetic rats,and reduce the expression of inflammatory factor and the accumulation of extracellular matrix via inhibiting the expression of Notch2 at protein level.

关 键 词：糖尿病肾病 NOTCH2 TOLL样受体4 NLRP3 Α-硫辛酸 炎症 

分 类 号：R-332[医药卫生] R322.61