益肾通络方对肾病综合征大鼠的药效作用及其分子机制研究
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摘要
目的探讨益肾通络方治疗肾病综合征大鼠和影响大鼠肾小球系膜细胞增殖的作用机制。
方法1.采用阳离子牛血清白蛋白复制肾病综合征大鼠模型,随机分为5组,即模型组,对照组(肾炎四味片组),益肾通络方低、中、高剂量组,每组各10只,并以10只同批正常大鼠为正常组。分别测定大鼠24小时尿蛋白,血清白蛋白,血肌酐,血尿素氮;观察大鼠肾组织病理形态,测定面积比;免疫组织化学方法检测大鼠肾组织白细胞介素-6(IL-6)、转化生长因子-β1(TGF-β1)、Smad7的分布和含量。2.制备益肾通络方大鼠血清,以脂多糖为刺激因子,将体外大鼠肾小球系膜细胞分为5组,即空白组、模型组(脂多糖组)、益肾通络方低、中、高剂量组。以甲基偶氮唑盐法(MTT)检测系膜细胞增殖情况,以逆转录-聚合酶链反应方法(RT-PCR)检测系膜细胞IL-6、TGF-β1、Smad7信使核糖核酸(mRNA)表达。
结果1.益肾通络方各剂量组24小时尿蛋白含量、血清肌酐、血尿素氮下降(P＜0.01);血清白蛋白提高(P＜0.01);肾脏病理损害均有不同程度减轻,面积比减少(P＜0.01);IL-6、TGF-β1在肾组织的沉积减少,Smad7在肾组织的表达提高,其作用优于模型组和肾炎四味片组,以益肾通络方中、高剂量为佳(P＜0.05,P＜0.01)。2.IL-6与TGF-β1呈线性正相关(P＜0.01),Smad7与IL-6或TGF-β1呈负相关(P＜0.05,P＜0.01)。3.益肾通络方含药血清对体外大鼠肾小球系膜细胞增殖有明显抑制作用(P＜0.05,P＜0.01),以高剂量为佳(P＜0.01);高剂量含药血清组Smad7mRNA的表达明显上调,而IL-6mRNA和TGF-β1mRNA的表达下调(P＜0.01)。
结论1.益肾通络方对肾病综合征大鼠有良好的治疗作用,能改善相关蛋白,改善。肾功能,减轻肾脏病理损害;其作用机制之一在于抑制肾小球系膜细胞增殖。2.益肾通络方能有效地抑制肾小球系膜细胞增殖;调节Smad7/TGF-β1/IL-6三者之间的相互作用是其分子机制之一。3.肾虚夹瘀是肾病综合征的基本病机,补肾化瘀是肾病综合征的主要治法。4.益肾通络方是治疗肾病综合征的有效方剂。
Objective To study the effective mechanism of Yishentongluo on treating rats with nephrotic syndrome and restraining the proliferation in rat mesangial cells.
Methods 1.50 rat models made by cationic bovine serum albumin(C-BSA) were devided into five groups at random,including the pathological pattern group,the control group(Shenyansiweipian,SYSW), low-dosage Yishentongluofang(YSTL) group,middle-dosage group,and high-dosage group.Each experimental group consisted of 10 rats and the normal group contained 10 normal rats in the same batch.All rats were examined 24 hours later for urine protein quantity(24huPro),albumin(Alb), serum creatinine(Scr) and blood urea nitrogen(BUN).Their pathological form were also observed and positive area ratio examined.Furthermore, they were examined the distribution and quantity of interleukin-6(IL-6), transforming growth factor-beta 1(TGF-β) and Smad7 with immunohistochemistry in kidney.2.The serum of YSTL was made.With lipase as stimulating factor,the mesangial cells(MC) cultured were divided into five groups,including the control(normal serum),the pathological pattern(lipase,LPS),low-dosage,middle-dosage and high-dosage YSTL group.The proliferation in rat MC was examined with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide).IL-6 messenger ribonucleic acid(mRNA),TGF-β1mRNA and Smad7mRNA were also examined with reverse transcription-polymerase chain reaction(RT-PCR).
Results 1.In YSTL groups,the 24huPro,Scr and BUN decreased, while Alb increased.Also,in YSTL groups,the pathological damage, positive area ratio,the deposition of IL-6 and TGF-β1 decreased and Smad7 increased in kidney.They(especially the middle-dosage and high-dosage group) were much better than either the pathological pattern group or SYSW one respectively(P<0.05,P<0.01).2.There was a positive linear correlation between IL-6 and TGF-β1(P<0.01),but a negative one between Smad7 and either IL-6 or TGF-β1(P<0.05,P<0.01).3.The serum of YSTL,especially the high-dosage one,restrained the proliferation in rat MC better(P<0.05,P<0.01).The expression of Smad7mRNA was promoted in high-dosage serum group,but IL-6mRNA and TGF-β1mRNA were descended(P<0.01).
Conclusion 1.YSTL had obvious effects on rats with nephrotic syndrome(NS).It could improve the relative proteins and the functions of kidney,and reduce the pathological damages.One of its mechanism might be restraining the proliferation in rat MC.2.YSTL could restrain the proliferation in rat MC effectively.One of its molecular mechanism was adjusting the relations among Smad7/TGF-β1/IL-6.3.The basic pathogenesis of NS is deficiency of the kidney accompanied with blood-stasis.The main methods of treatment is reinforcing the kidney and eliminating the stasis.4.YSTL is an effective pharmaceutical.
方法1.采用阳离子牛血清白蛋白复制肾病综合征大鼠模型,随机分为5组,即模型组,对照组(肾炎四味片组),益肾通络方低、中、高剂量组,每组各10只,并以10只同批正常大鼠为正常组。分别测定大鼠24小时尿蛋白,血清白蛋白,血肌酐,血尿素氮;观察大鼠肾组织病理形态,测定面积比;免疫组织化学方法检测大鼠肾组织白细胞介素-6(IL-6)、转化生长因子-β1(TGF-β1)、Smad7的分布和含量。2.制备益肾通络方大鼠血清,以脂多糖为刺激因子,将体外大鼠肾小球系膜细胞分为5组,即空白组、模型组(脂多糖组)、益肾通络方低、中、高剂量组。以甲基偶氮唑盐法(MTT)检测系膜细胞增殖情况,以逆转录-聚合酶链反应方法(RT-PCR)检测系膜细胞IL-6、TGF-β1、Smad7信使核糖核酸(mRNA)表达。
结果1.益肾通络方各剂量组24小时尿蛋白含量、血清肌酐、血尿素氮下降(P＜0.01);血清白蛋白提高(P＜0.01);肾脏病理损害均有不同程度减轻,面积比减少(P＜0.01);IL-6、TGF-β1在肾组织的沉积减少,Smad7在肾组织的表达提高,其作用优于模型组和肾炎四味片组,以益肾通络方中、高剂量为佳(P＜0.05,P＜0.01)。2.IL-6与TGF-β1呈线性正相关(P＜0.01),Smad7与IL-6或TGF-β1呈负相关(P＜0.05,P＜0.01)。3.益肾通络方含药血清对体外大鼠肾小球系膜细胞增殖有明显抑制作用(P＜0.05,P＜0.01),以高剂量为佳(P＜0.01);高剂量含药血清组Smad7mRNA的表达明显上调,而IL-6mRNA和TGF-β1mRNA的表达下调(P＜0.01)。
结论1.益肾通络方对肾病综合征大鼠有良好的治疗作用,能改善相关蛋白,改善。肾功能,减轻肾脏病理损害;其作用机制之一在于抑制肾小球系膜细胞增殖。2.益肾通络方能有效地抑制肾小球系膜细胞增殖;调节Smad7/TGF-β1/IL-6三者之间的相互作用是其分子机制之一。3.肾虚夹瘀是肾病综合征的基本病机,补肾化瘀是肾病综合征的主要治法。4.益肾通络方是治疗肾病综合征的有效方剂。
Objective To study the effective mechanism of Yishentongluo on treating rats with nephrotic syndrome and restraining the proliferation in rat mesangial cells.
Methods 1.50 rat models made by cationic bovine serum albumin(C-BSA) were devided into five groups at random,including the pathological pattern group,the control group(Shenyansiweipian,SYSW), low-dosage Yishentongluofang(YSTL) group,middle-dosage group,and high-dosage group.Each experimental group consisted of 10 rats and the normal group contained 10 normal rats in the same batch.All rats were examined 24 hours later for urine protein quantity(24huPro),albumin(Alb), serum creatinine(Scr) and blood urea nitrogen(BUN).Their pathological form were also observed and positive area ratio examined.Furthermore, they were examined the distribution and quantity of interleukin-6(IL-6), transforming growth factor-beta 1(TGF-β) and Smad7 with immunohistochemistry in kidney.2.The serum of YSTL was made.With lipase as stimulating factor,the mesangial cells(MC) cultured were divided into five groups,including the control(normal serum),the pathological pattern(lipase,LPS),low-dosage,middle-dosage and high-dosage YSTL group.The proliferation in rat MC was examined with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide).IL-6 messenger ribonucleic acid(mRNA),TGF-β1mRNA and Smad7mRNA were also examined with reverse transcription-polymerase chain reaction(RT-PCR).
Results 1.In YSTL groups,the 24huPro,Scr and BUN decreased, while Alb increased.Also,in YSTL groups,the pathological damage, positive area ratio,the deposition of IL-6 and TGF-β1 decreased and Smad7 increased in kidney.They(especially the middle-dosage and high-dosage group) were much better than either the pathological pattern group or SYSW one respectively(P<0.05,P<0.01).2.There was a positive linear correlation between IL-6 and TGF-β1(P<0.01),but a negative one between Smad7 and either IL-6 or TGF-β1(P<0.05,P<0.01).3.The serum of YSTL,especially the high-dosage one,restrained the proliferation in rat MC better(P<0.05,P<0.01).The expression of Smad7mRNA was promoted in high-dosage serum group,but IL-6mRNA and TGF-β1mRNA were descended(P<0.01).
Conclusion 1.YSTL had obvious effects on rats with nephrotic syndrome(NS).It could improve the relative proteins and the functions of kidney,and reduce the pathological damages.One of its mechanism might be restraining the proliferation in rat MC.2.YSTL could restrain the proliferation in rat MC effectively.One of its molecular mechanism was adjusting the relations among Smad7/TGF-β1/IL-6.3.The basic pathogenesis of NS is deficiency of the kidney accompanied with blood-stasis.The main methods of treatment is reinforcing the kidney and eliminating the stasis.4.YSTL is an effective pharmaceutical.
引文
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