贵州医科大学学报

2018, v.43;No.209(02) 167-173

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水飞蓟宾对肾间质纤维化的治疗作用及机制
The Therapeutic Effect and Mechanism of Silybin on Renal Interstitial Fibrosis

刘畅;朱春玲;严瑞;程全伟;
LIU Chang;ZHU Chunling;YAN Rui;CHENG Quanwei;Department of Nephrology,The Affiliated Hospital of Guizhou Medical University;Department of Nephrology,the First People's Hospital of Guiyang City;

摘要(Abstract):

目的:研究水飞蓟宾对肾间质纤维化模型大鼠的保护作用及机制。方法:8周龄雄性SD大鼠36只,随机分成假手术组、模型组及治疗组,模型组及治疗组采用左侧输尿管梗阻方法复制肾间质纤维化模型,假手术组大鼠只做手术(不结扎输尿管),治疗组造模同时给予灌胃水飞蓟宾至处死前[200 mg/(kg·d)],假手术组和模型组注射等量生理盐水灌胃;各组大鼠分别于术后第7和14天处死(6只/组),取肾组织行HE染色观察大鼠肾组织病理改变、Masson染色以观察各组大鼠肾间质胶原的沉积,行免疫组化染色观察观察大鼠肾脏组织切片中Ski、转化生长因子-β1(TGF-β1)、smad3及纤维连结蛋白(FN)的表达;Western Blot检测肾脏组织匀浆中Ski、TGF-β1、smad3、FN蛋白表达水平,Pearson法分析Ski与TDI、TFI、TGF-β1、smad3及FN表达的相关性。结果:HE、Masson染色结果显示,假手术组大鼠肾小球、肾小管未见异常,模型组大鼠HE染色可见肾小管上皮细胞肿胀、空泡变性及基底膜增厚,Masson染色肾小管、肾间质可见纤维阳性染色,第14天时更严重;治疗组各时点肾脏病变程度均较同期模型组减轻,模型组大鼠的TDI和TFI评分均高于假手术组,治疗组较模型组有所降低,第14天时变化更大(P<0.05);肾脏组织免疫组化结果显示,与假手术组比较,模型组SKi表达明显减少,TGF-β1、smad3及FN表达明显升高,第14天时变化更明显(P<0.05);与模型组比较,治疗组Ski有所增加,但仅第14天差异有统计学意义(P<0.05),TGF-β1、smad3、FN显显著降低,第14天组更为明显(P<0.05);肾脏组织匀浆Western Blot结果显示,与假手术组比较,模型组SKi表达少明显减,TGF-β1、smad3、FN表达明显升高,第14天时变化更明显(P<0.05);与模型组比较,治疗组Ski显著增加,TGF-β1、smad3、FN显显著降低,第14天组时变化更明显(P<0.05);Pearson相关分析显示,Ski表达与TDI、TFI、TGF-β1、smad3、FN均呈显著负相关(P<0.05)。结论:水飞蓟宾可能通过上调Ski阻遏TGF-β/smad信号通路改善肾间质纤维化模型大鼠的肾间质纤维化过程。
Objective:To study the protective effect and mechanism of silybin on rat model of renal interstitial fibrosis.Methods:Thirty-six normal male Sprague-Dawley rats were divided into 3 groups randomly,sham operation group(group S),unilateral ureteral obstruction(UUO) model group(group U),Silybin(200 mg/kg) therapy group(group D).The left ureter of rats in group U and group D were ligatured to establish renal interstitial fibrosis model.The rats in group S were only given operation(left ureter was not ligatured),and at the same time of modeling,the group D was given silybin[200 mg/(kg·D) ]by gavage till execution.Rats in group U and group S were given equal amount of saline by gavage.Rats of each group were killed at the 7 thday and the 14 thday after operation respectively.HE staining was used to observe the renal pathological change.Masson staining was used to evaluate the accumulation of collagen protein.Expression of oncoprotein(Ski),transforming growth factor-beta 1(TGF-beta 1),Smad3 and fibronectin(FN) in rat kidney tissue section were detected by immunohistochemistry.Western Blot was used to examine the expression of Ski,TGF-β1,Smad3 and FN.Pearson method was used to analyze the correlation of Ski with TDI,TFI,TGF-β1,Smad3,and FN expression.Results:HE and Masson staining showed that glomerulus and renal tubules of the rats in group S were normal.HE staining of rats in group U showed renal tubular epithelial cell swelling and vacuolar degeneration and basement membrane thickening,Masson staining showed fiber positively staining in renal tubule and renal interstitium,the changes were more serious at the 14 thday; The degree of renal lesions at each time point in group D was lower than that in the same period of group U.The TDI and TFI scores in group U were all higher than those in group S,group D was lower than that in group U,and the change was more significant on the fourteenth day.Immunohistochemistry showed that compared with group S,the expression of SKi in group U was significantly reduced,and the expression of TGF-β1,Smad3 and FN increased significantly,and the change was more obvious on the fourteenth day(P < 0.05); Immunohistochemistry also showed that compared with group U,the Ski in group D increased,but the difference was statistically significant only on the fourteenth day(P < 0.05); TGF-β1,Smad3 and FN were significantly decreased,while those in the fourteenth day were more obvious(P < 0.05).Western blot showed that compared with group S,the expression of SKi in group U was significantly reduced,and the expression of TGF-β1,Smad3 and FN increased significantly,and the change was more obvious on the fourteenth day(P < 0.05); Compared with group U,the Ski in group D increased,TGF-β1,Smad3 and FN were significantly decreased,while those in the fourteenth day were more obvious(P < 0.05).Pearson correlation analysis showed that the expression of Ski was negatively correlated with TDI,TFI,TGF-beta 1,Smad3 and FN(P < 0.05).Conclusions:Silybin possibly delay the progression of renal interstitial fibrosis by up-regulating Ski and inhibition of TGFβ/samds signaling pathway.

关键词(KeyWords): 肾间质纤维化;ski;TGF-β/smad信号通路;水飞蓟宾;单侧输尿管梗阻;模型,动物;大鼠,Sprague Dawley
renal interstitial fibrosis;Ski;TGF-β1/smads signaling pathway;Silybin;unilateral ureteral obstruction;model,animal;rats,Sprague-Dawley

Abstract:

Keywords:

基金项目(Foundation): 贵州省科技厅社发攻关项目[黔科合SY字(2014)3021号];贵州省科技厅联合基金项目[黔科合LH字(2014)7124号];; 贵州省卫计委科技基金项目(gzwjki2014-1-007);; 贵阳市卫计委科学技术计划项目(2015筑卫科技合同字第018号)

作者(Author): 刘畅;朱春玲;严瑞;程全伟;
LIU Chang;ZHU Chunling;YAN Rui;CHENG Quanwei;Department of Nephrology,The Affiliated Hospital of Guizhou Medical University;Department of Nephrology,the First People's Hospital of Guiyang City;

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DOI: 10.19367/j.cnki.1000-2707.2018.02.008

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