直接肾素抑制剂阿利吉仑对肾纤维化小鼠上皮-间质转化的调节作用

doi:10.13481/j.1671-587x.20170104

吉林大学学报(医学版) ›› 2017, Vol. 43 ›› Issue (01): 16-20.doi: 10.13481/j.1671-587x.20170104

直接肾素抑制剂阿利吉仑对肾纤维化小鼠上皮-间质转化的调节作用

邓海月, 于方, 姜红

中国医科大学附属第一医院儿科, 辽宁沈阳 110001

收稿日期:2016-03-05 出版日期:2017-01-28 发布日期:2017-02-08
通讯作者: 姜红,教授,博士研究生导师(Tel:024-83282527,E-mail:jianghong724@163.com) E-mail:jianghong724@163.com
作者简介:邓海月(1990-),女,河北省唐山市人,医学硕士,主要从事小儿肾脏疾病的基础和临床方面的研究。
基金资助:
高等学校博士学科点专项科研基金资助课题（20122104110001）；辽宁省沈阳市科技局科技计划项目资助课题（F16-206-9-44）

Regulatory effect of direct renin inhibitor aliskiren on epithelial-mesenchymal transition of renal fibrosis mice

DENG Haiyue, YU Fang, JIANG Hong

Department of Pediatrics, First Affiliated Hospital, China Medical University, Shenyang 110001, China

Received:2016-03-05 Online:2017-01-28 Published:2017-02-08

摘要/Abstract

摘要：

目的：探讨直接肾素抑制剂阿利吉仑对单侧输尿管结扎引起的小鼠肾纤维化中上皮-间质转化（EMT）的调节作用，阐明阿利吉仑抗肾纤维化的作用机制。方法：24只雄性ICR小鼠分为假手术组、模型组和阿利吉仑干预组，采用单侧输尿管结扎方法制作小鼠肾纤维化模型。HE染色观察小鼠肾间质纤维化的病理组织形态，Masson染色观察小鼠肾间质纤维化中胶原蛋白的表达情况，免疫组织化学染色法观察胞浆中α平滑肌肌动蛋白（α-SMA）的表达，免疫印迹法检测小鼠肾组织中E钙黏蛋白（E-cad）、α-SMA和Ⅰ型胶原（Col Ⅰ）的表达水平。结果：通过单侧输尿管结扎方法成功制备小鼠肾纤维化模型。HE染色和Masson染色，与模型组比较，阿利吉仑干预组小鼠肾纤维化程度明显降低，胶原蛋白表达明显减少。免疫组织化学染色，阿利吉仑干预组小鼠肾小管间质纤维化区域胞浆内α-SMA阳性显色较模型组明显减少。免疫印迹法，模型组小鼠肾组织中α-SMA和Col Ⅰ蛋白表达水平升高，分别是假手术组的1.79倍和1.95倍；E-cad蛋白表达水平降低，为假手术组的37.23%，组间比较差异有统计学意义（P<0.05）；阿利吉仑干预组小鼠肾组织中α-SMA和Col Ⅰ蛋白表达水平降低，E-cad蛋白表达水平升高，分别是模型组的63.72%、65.54%和2.1倍，组间比较差异均有统计学意义（P<0.05）。结论：阿利吉仑能够通过上调E-cad的表达同时下调α-SMA、Col Ⅰ的表达抑制小鼠肾纤维化中EMT，进而发挥抗纤维化的作用。

关键词: α平滑肌肌动蛋白, 阿利吉仑, 上皮-间质转化, E钙黏蛋白, 肾纤维化

Abstract:

Objective: To explore the regulatory effect of direct renin inhibitor aliskiren on epithelial-mesenchymal transition(EMT) of the renal fibrosis mice induced by unilateral ureteral occlusion,and to clarify its mechanisms of inhibiting renal fibrosis.Methods: Twenty-four ICR mice were divided into sham group,model group, and aliskiren intervention group. The renal fibrosis models were established by unilateral ureteral occlusion.The pathohistomorphology of renal interstitial fibrosis was observed by HE staining.The collagen protein expression in renal interstitial was observed by Masson staining.The α-smooth muscle actin(α-SMA) expression in the cytoplasm was observed by immnocytochemical staining.The protein expression levels of E-cadherin (E-cad), α-SMA,and type Ⅰ collagen(Col Ⅰ) in the kidney tissue of the mice were detected by Western blotting method.Results: The mouse models of renal fibrosis were successfully produced by unilateral ureteral occlusion.The HE staining and Masson staining results showed that the degree of mouse renal interstitial fibrosis in alikiren intervention group was decreased and the expression level of collagen was reduced compared with model group.The immnocytochemical staining results showed that the expression of α-SMA in renal interstitial fibrosis area in alikiren intervention group was obviously reduced compared with model group.The results of Western blotting methods showed that the expression levels of α-SMA and Col Ⅰ in model group were increased to 1.79 folds and 1.95 folds compared with sham group(P<0.05),while the expression level of E-cad was decreased to 37.23%(P<0.05);the expressions levels of α-SMA and Col Ⅰ were decreased to 63.72% and 65.54% compared with model group(P<0.05),while the expression level of E-cad was increased to 2.1 folds(P<0.05).Conclusion: Aliskiren can inhibit the EMT of renal fibrosis produced by unilateral ureteral occlusion via up-regulation of E-cad expression and down-regulation of expressions of α-SMA and Col Ⅰ.

Key words: α-smooth muscle actin, aliskiren, epithelial-mesenchymal transition, E-cadherin, kidney fibrosis

中图分类号:

R-332

邓海月, 于方, 姜红. 直接肾素抑制剂阿利吉仑对肾纤维化小鼠上皮-间质转化的调节作用[J]. 吉林大学学报(医学版), 2017, 43(01): 16-20.

DENG Haiyue, YU Fang, JIANG Hong. Regulatory effect of direct renin inhibitor aliskiren on epithelial-mesenchymal transition of renal fibrosis mice[J]. Journal of Jilin University Medicine Edition, 2017, 43(01): 16-20.

参考文献

[1] Benzoubir N,Mussini C,Lejamtel C,et al.Gamma-smooth muscle actin expression is associated with epithelial-mesenchymal transition and stem-Like properties in hepatocellular carcinoma[J].PLoS One,2015,10(6):e0130559.
[2] Xia H,Chen J,Shi M,et al.EDIL3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma[J].J Hepatol,2015,63(4):863-873.
[3] Lovisa S,LeBleu VS,Tampe B,et al.Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis[J].Nat Med,2015,21(9):998-1009.
[4] Morizane R,Fujii S,Monkawa T,et al.miR-34c attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction[J].Sci Rep,2014,3(4):4578.
[5] Robles NR,Cerezo I,Hernandez-Gallego R.Renin-angiotensin system blocking drugs[J].J Cardiovasc Pharmacol Ther,2014,19(1):14-33.
[6] Yang J,Liu Y.Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis[J].J Am Soc Nephrol,2002,13(1):96-107.
[7] Sharma A,Khan M,Levick S,et al.Novel omega-3 fatty acid epoxygenase metabolite reduces kidney fibrosis[J].Int J Mol Sci,2016,17(5):751.
[8] Li S,Shi S,Wei J,et al.Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition[J].Am J Transl Res,2016,8(2):460-472.
[9] Iwano M,Plieth D,Danoff TM,et al.Evidence that fibroblasts derive from epithelium during tissue fibrosis[J].J Clin Invest,2002,110(3):341-350.
[10] 钱明,甘卫华,陈荣华,等.外源性结缔组织生长因子对肾小管上皮细胞的转分化和胶原合成效应[J].中国当代儿科杂志,2006,8(2):144-146.
[11] Pan J,Zhang J,Zhang X,et al.Role of microRNA-29b in angiotensin Ⅱ-induced epithelial-mesenchymal transition in renal tubular epithelial cells[J].Int J Mol Med,2014,34(5):1381-1387.
[12] Chen HY,Zhong X,Huang XR,et al.MicroRNA-29b inhibits diabetic nephropathy in db/db mice[J].Mol Ther,2014,22(4):842-853.
[13] Kapinas K,Kessler CB,Delany AM.miR-29 suppression of osteonectin in osteoblasts:regulation during differentiation and by canonical Wnt signaling[J].J Cell Biochem,2009,108(1):216-224.
[14] Sapkota GP.The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1[J]. Open Biol, 2013,3(6):130067.
[15] Luna C,Li G,Qiu J,et al.Cross-talk between miR-29 and transforming growth factor-betas in trabecular meshwork cells[J].Invest Ophthalmol Vis Sci,2011,52(6):3567-3572.
[16] Pan J,Zhang J, Zhang X,et al.Role of microRNA-29b in angiotensin II-induced epithelial-mesenchymal transition in renal tubular epithelial cells[J].Int J Mol Med,2014,34(5):1381-1387.
[17] 韩红,孙东,麻艳艳,等.单侧输尿管梗阻模型小鼠肾脏微血管损伤与肾间质纤维化的关系研究[J].中国病理生理杂志,2010,26(12):2478-2481,2486.
[18] Vardeny O,Pouleur AC,Takeuchi M,et al.Influence of diabetes on efficacy of aliskiren,losartan or both on left ventricular mass regression[J].J Renin Angiotensin Aldosterone Syst,2012,13(2):265-272
[19] Abe M,Suzuki H,Okada K,et al.Efficacy analysis of the renoprotective effects of aliskiren in hypertensive patients with chronic kidney disease[J].Heart Vessels,2013,28(4):442-452.
[20] Imbalzano E,Scarpelli M,Mandraffino G,et al.Combination therapy with aliskiren versus ramipril or losartan added to conventional therapy in patients with type 2 diabetes mellitus,uncontrolled hypertension and microalbuminuria[J].J Renin Angiotensin Aldosterone Syst,2015,16(4):956-964.
[21] 康阳阳,刘章锁,刘东伟.中国成人慢性肾脏病患病率荟萃分析[J].中国实用内科杂志,2016,36(9):785-789.

直接肾素抑制剂阿利吉仑对肾纤维化小鼠上皮-间质转化的调节作用

Regulatory effect of direct renin inhibitor aliskiren on epithelial-mesenchymal transition of renal fibrosis mice

RichHTML

PDF (PC)

赞

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 8

Metrics

本文评价

推荐阅读 0

[1]	赵丽艳, 宋扬, 吕晓艳, 贾茗博, 朱洪权. 上皮-间质转化胶质瘤细胞的干细胞样特性及白藜芦醇对其干细胞样特性的抑制作用[J]. 吉林大学学报(医学版), 2018, 44(06): 1185-1189.
[2]	赵丽艳, 宋扬, 陈勇, 吕晓艳, 贾茗博, 李蕴潜. 白藜芦醇对胶质瘤U87细胞上皮-间质转化的抑制作用[J]. 吉林大学学报(医学版), 2018, 44(05): 943-948.
[3]	宋扬, 赵丽艳, 李蕴潜, 陈勇. 胶质瘤细胞上皮-间质转化及靶向抑制策略的研究进展[J]. 吉林大学学报(医学版), 2017, 43(05): 1064-1068.
[4]	宋扬, 赵丽艳, 陈勇, 吕晓艳, 崔佳乐, 李蕴潜, 赵刚. TGF-β1对胶质瘤U87细胞上皮-间质转化的诱导作用[J]. 吉林大学学报(医学版), 2016, 42(06): 1087-1091.
[5]	史毅，吴伟忠，金晓红，张斌. α-catulin和E-cadherin在舌鳞状细胞癌组织中的表达及其临床意义[J]. 吉林大学学报(医学版), 2014, 40(04): 838-841.
[6]	穆媛\|庄映辉. 环孢菌素A对链脲佐菌素诱导的糖尿病大鼠肾脏组织中MIP-1&alpha\|mRNA表达的影响[J]. J4, 2012, 38(4): 683-686.
[7]	尚静\|房宁\|滕思莹\|崔香艳\|汪欣. 喉鳞状细胞癌组织中Snail和E-cadherin的表达及其意义[J]. J4, 2012, 38(2): 315-319.
[8]	曲萌\|王丹\| 李才\|李相军,苗春生\|李蕴潜. 尾加压素Ⅱ和组织型转谷氨酰胺酶在大鼠肾间质纤维化组织中的表达及意义[J]. J4, 2011, 37(2): 207-210.