苯那普利和氯沙坦对肾间质纤维化幼鼠组织型转谷氨酰胺酶和转化生长因子-β_1的抑制作用
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摘要
目的探讨苯那普利和氯沙坦对肾间质纤维化幼鼠组织型转谷氨酰胺酶(tTG)和转化生长因子-β_1(TGF-β_1)的抑制作用。方法雄性wistar幼鼠60只随机分为对照组、模型组和干预组,每组20只。对模型组和干预组幼鼠建立单侧输尿管结扎模型,干预组从建模后第2天起灌胃给予苯那普利和氯沙坦各6mg/(kg·d),1次/天,对照组和模型组灌胃给予等量生理盐水。于实验开始后第3、7、14、28天每组取5只鼠制成标本进行HE染色、Masson染色,采用非生物素标记的PV6001二步法,检测3组肾组织tTG、TGF-β_1的表达。结果 Masson染色结果显示对照组肾间质纤维化面积较小,模型组肾间质纤维化面积显著增加,干预组小部分纤维化面积较模型组降低,差异有统计学意义(P<0.01)。对照组TGF-β_1和tTG表达在对照组较少,模型组高表达,干预组较模型组有所减少,3组比较差异有统计学意义(P<0.01),且随着时间增加,模型组和干预组幼鼠TGF-β_1和tTG表达上升,差异有统计学意义。模型组幼鼠tTG水平与Masson染色面积呈正相关关系(r=0.854,P<0.01);tTG水平与TGF-β_1水平呈正相关关系(r=0.813,P<0.01)。结论肾间质纤维化过程中tTG与TGF-β_1呈正相关关系,苯那普利和氯沙坦抗纤维化作用可能与抑制tTG与TGF-β_1有关。
Objective To investigate the inhibitory effects of benazepril and losartan on tissue transglutaminase(tTG)and transforming growth factor-β_1(TGF-β_1)in young rats with renal interstitial fibrosis.Methods Sixty male wistar rats were randomly divided into control group,model group and intervention group.The model of unilateral ureteral ligation was established in the model group and the intervention group.The intervention group received benazepril and losartan 6 mg/(kg·d),1 time/d from the 2nd day after the modeling.And the model group and control group were given the same amount of saline.At the 3rd,7th,14th and 28th day after the start of the experiment,5 mice were sacrificed by HE staining and Masson staining.The non-biotin-labeled PV6001 two-step method was used to detect the expression of tTG and TGF-expression.Results Masson staining showed that the area of interstitial fibrosis was smaller in the control group,and was significantly increased in the model group,and was lower in the intervention group than that of the model group(P<0.01).The expression of TGF-β_1 and tTG was little in the control group,was high in the model group,and the expression in intervention group was lower than that of the model group,the difference was statistically significant(P<0.01).The expression of TGF-β_1 and tTG in the young rats were increased with the time(P<0.01).There was a positive correlation between tTG level and Masson staining area(r=0.854,P<0.01).There was a positive correlation between tTG level and TGF-β_1 level(r=0.813,P<0.01).Conclusion tTG is positively correlated with TGF-β_1,and tTG can induce fibrosis by up-regulating TGF-β_1.The benazepril and losartan can play an anti-fibrosis effect by inhibiting TGF-β_1 and tTG.
Objective To investigate the inhibitory effects of benazepril and losartan on tissue transglutaminase(tTG)and transforming growth factor-β_1(TGF-β_1)in young rats with renal interstitial fibrosis.Methods Sixty male wistar rats were randomly divided into control group,model group and intervention group.The model of unilateral ureteral ligation was established in the model group and the intervention group.The intervention group received benazepril and losartan 6 mg/(kg·d),1 time/d from the 2nd day after the modeling.And the model group and control group were given the same amount of saline.At the 3rd,7th,14th and 28th day after the start of the experiment,5 mice were sacrificed by HE staining and Masson staining.The non-biotin-labeled PV6001 two-step method was used to detect the expression of tTG and TGF-expression.Results Masson staining showed that the area of interstitial fibrosis was smaller in the control group,and was significantly increased in the model group,and was lower in the intervention group than that of the model group(P<0.01).The expression of TGF-β_1 and tTG was little in the control group,was high in the model group,and the expression in intervention group was lower than that of the model group,the difference was statistically significant(P<0.01).The expression of TGF-β_1 and tTG in the young rats were increased with the time(P<0.01).There was a positive correlation between tTG level and Masson staining area(r=0.854,P<0.01).There was a positive correlation between tTG level and TGF-β_1 level(r=0.813,P<0.01).Conclusion tTG is positively correlated with TGF-β_1,and tTG can induce fibrosis by up-regulating TGF-β_1.The benazepril and losartan can play an anti-fibrosis effect by inhibiting TGF-β_1 and tTG.
引文
[1]孙阳,赵艳红,卢永新,等.肾脏纤维化的发病机制及治疗进展[J].实用临床医药杂志,2015,19(9):173-176.
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[7]茶春丽,代留玲,陈国姝,等.新纤维化相关因子SFTPA2与UUO模型大鼠肾间质纤维化关系的研究[J].中国社区医师,2016,32(24):7-9.
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[9]SUN N,ZHAI L,LI H,et al.Angiotensin-converting enzyme Inhibitor(ACEI)-mediated amelioration in renal fibrosis involves suppression of mast cell degranulation[J].Kidney Blood Press Res,2016,41(1):108-118.
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[12]李娜,孙建平,高延霞,等.缺氧诱导因子-1α在肾间质纤维化中的表达及意义[J].中国中西医结合肾病杂志,2012,13(1):18-21.
[13]袁静,杨霞,龙艳君,等.厄贝沙坦对单侧输尿管梗阻大鼠肾组织缺氧诱导因子1α和结缔组织生长因子表达的影响[J].中华肾脏病杂志,2013,29(2):119-123.
[14]车丽双,黄荣桂.TGF-β1与CTGF在肾间质纤维化中的作用[J].医学综述,2013,19(4):624-626.
[15]崔峥,马晓燕.TGF-β1/Smad号通路在腺嘌呤导致的肾纤维化大鼠肾脏组织中的作用与意义[J].湖南中医杂志,2016,32(4):158-160.
[16]郭碧林,朱春玲.Egr-1蛋白、MMP-2、TGF-β1在肾小管间质纤维化大鼠中的表达及意义[J].中国现代医学杂志,2013,23(7):27-33.
[17]张文军.慢肾康宁对UUO大鼠肾间质纤维化中TGF-β1/Smad3信号调控的miR-21、miR-29表达的影响[D].广州:暨南大学,2015.
[18]刘森炎,钱一欣,卞蓉蓉,等.结缔组织生长因子通过上调肾间质成纤维细胞组织型转谷氨酰胺酶和Ⅲ型胶原蛋白促进肾间质纤维化[J].上海医学,2017,40(3):173-178.
[2]贾慧,李缨,金惠良.血、尿RBP水平判断原发性肾病综合征肾脏损伤程度和预后的价值[J].山东医药,2014,54(13):19-21.
[3]孔勤,李平.MicroRNAs在肾脏纤维化中的研究进展[J].中国中西医结合肾病杂志,2016,17(6):546-550.
[4]王华,赵婷婷,张浩军,等.TGF-β信号通路抑制剂对肾脏纤维化的治疗作用[J].中国中西医结合肾病杂志,2016,17(2):177-180.
[5]SONODA Y,GOHDA T,SUZUKI Y,et al.Circulating TNF receptors 1and 2are associated with the severity of renal interstitial fibrosis in IgA nephropathy[J].PLoS One,2015,10(4):e0122212.
[6]毕慧欣,刘瑞洪,孙林,等.热休克蛋白47在转化生长因子β1刺激的肾小管上皮细胞转分化中的作用[J].中华肾脏病杂志,2013,29(10):775-781.
[7]茶春丽,代留玲,陈国姝,等.新纤维化相关因子SFTPA2与UUO模型大鼠肾间质纤维化关系的研究[J].中国社区医师,2016,32(24):7-9.
[8]曲萌,王丹,李才,等.组织型转谷氨酰胺酶在单侧输尿管梗阻大鼠肾脏中的表达及意义[J].中国实验诊断学,2012,15(2):220-223.
[9]SUN N,ZHAI L,LI H,et al.Angiotensin-converting enzyme Inhibitor(ACEI)-mediated amelioration in renal fibrosis involves suppression of mast cell degranulation[J].Kidney Blood Press Res,2016,41(1):108-118.
[10]CHOW B S,KOCAN M,BOSNYAK S,et al.Relaxin requires the angiotensinⅡtype 2receptor to abrogate renal interstitial fibrosis[J].Kidney Int,2014,86(1):75-85.
[11]JIANG G T,CHEN X,LI D,et al.Ulinastatin attenuates renal interstitial inflammation and inhibits fibrosis progression in rats under unilateral ureteral obstruction[J].Mol Med Rep,2014,10(3):1501-1508.
[12]李娜,孙建平,高延霞,等.缺氧诱导因子-1α在肾间质纤维化中的表达及意义[J].中国中西医结合肾病杂志,2012,13(1):18-21.
[13]袁静,杨霞,龙艳君,等.厄贝沙坦对单侧输尿管梗阻大鼠肾组织缺氧诱导因子1α和结缔组织生长因子表达的影响[J].中华肾脏病杂志,2013,29(2):119-123.
[14]车丽双,黄荣桂.TGF-β1与CTGF在肾间质纤维化中的作用[J].医学综述,2013,19(4):624-626.
[15]崔峥,马晓燕.TGF-β1/Smad号通路在腺嘌呤导致的肾纤维化大鼠肾脏组织中的作用与意义[J].湖南中医杂志,2016,32(4):158-160.
[16]郭碧林,朱春玲.Egr-1蛋白、MMP-2、TGF-β1在肾小管间质纤维化大鼠中的表达及意义[J].中国现代医学杂志,2013,23(7):27-33.
[17]张文军.慢肾康宁对UUO大鼠肾间质纤维化中TGF-β1/Smad3信号调控的miR-21、miR-29表达的影响[D].广州:暨南大学,2015.
[18]刘森炎,钱一欣,卞蓉蓉,等.结缔组织生长因子通过上调肾间质成纤维细胞组织型转谷氨酰胺酶和Ⅲ型胶原蛋白促进肾间质纤维化[J].上海医学,2017,40(3):173-178.