黄连素激活TGR5对高糖引起的肾小球系膜细胞纤维化的影响  

Effects of berberine on high glucose-induced fibrosis in glomerular mesangial cells by the activation of TGR5

作　　者：杨志英[1] 李学娟[2] 熊凤霄 王少贵 陈诚[1] 黄河清[1] 

机构地区：[1]中山大学药学院,广州5100008 [2]深圳市儿童医院药剂科,深圳518038

出　　处：《中药药理与临床》2016年第2期98-102,共5页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家自然科学基金(NO:81373457);国家科技重大专项子课题(NO:2014ZX09301307-008);教育部博士点基金(NO:20130171110097);广东省自然科学基金(NO:S2013010015765);广东省自然科学基金重点项目(NO:S2012020010991)的资助

摘　　要：目的:观察黄连素(Berberine,BBR)是否能够通过活化胆汁酸膜受体TGR5,从而抑制高糖引起的纤维连接蛋白FN的表达升高以及核因子AP-1的激活,改善由高糖引起的肾小球系膜细胞(GMCs)纤维化的发生。方法:采用小分子RNA干扰肾小球系膜细胞TGR5的蛋白表达,Western blot检测肾小球系膜细胞中TGR5、FN、ICAM-1、TGF-β1、p-c-Jun ser63、p-c-Jun ser73以及pc-Fos ser32蛋白水平。结果:30μmol/L黄连素能够明显抑制高糖培养的肾小球系膜细胞炎症因子(ICAM-1)和转化生长因子(TGF-β1)的表达,细胞外基质主要成分纤维连接蛋白(FN)生成明显减少。同样,给予黄连素处理后,能抑制HG诱导的c-Jun/cFos磷酸化水平。TGR5特异性激动剂INT-777能够剂量依赖性抑制高糖引起的FN、ICAM-1以及TGF-β1上调,并且10μmol/L的浓度下其抑制作用即具有显著性意义。而在干扰TGR5表达后,30μmol/L黄连素抑制高糖引起的FN、ICAM-1以及TGF-β1的作用被取消。结论:激活TGR5,抑制AP-1的活性可能是黄连素抑制高糖引起的FN、ICAM-1以及TGF-β1上调的分子机制之一。Objective： To observe whether berberine was able to attenuate the up- regulation of high glucose- induced fibronectin and nuclear factor AP-1 via activating the TGR5,eventually ameliorated renal fibrosis in glomerular mesangial cells（ GMCs）. Methods： Small interfering RNA was used to deplete the expression of TGR5 in GMCs. TGR5,FN,ICAM-1,TGF-β1,p-c-Jun ser63,p-c-Jun ser73 and p-c-Fos ser32 protein levels were detected by Western blot. Results： 30 μmol / L Berberine can inhibit the high glucose-induced intercellular adhesion molecule-1（ ICAM-1） and transforming growth factor（ TGF-β1） in GMCs,and fibronectin（ FN）,the main component of the extracellular matrix,was significantly reduced. After treatment of berberine,the c-Jun / c-Fos phosphorylation levels were suppressed. TGR5 specific agonist INT-777 can also significantly decrease FN,ICAM-1 and TGF-β1 expression in a dose-dependent manner with 10 μmol / L concentration. The effects of FN,ICAM-1 and TGF-β1 down-regulation by berberine in high glucose cultured GMCs was blocked after TGR5 knockdown using anti-TGR5 small interfering RNA. Conclusion： Berberine decreases FN,ICAM-1 and TGF-β1 levels under high glucose conditions in GMCs possibly by activating TGR5 and inhibiting AP-1 activity.

关 键 词：黄连素 TGR5 肾脏纤维化 转录因子AP-1 纤维连接蛋白FN 

分 类 号：R285[医药卫生—中药学]