从EMT角度探讨六味地黄汤干预5/6肾切除大鼠慢性肾衰的机制
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摘要
目的：研究5/6肾切除慢性肾衰竭大鼠肾小管上皮细胞EMT致肾间质纤维化的机理,探讨六味地黄汤抗肾间质纤维化的疗效机制。
方法：将健康雄性Sprapue-Demey大鼠随机分成正常组、假手术组、手术组。实验大鼠适应性喂养一周,采用5/6肾切除法复制慢性肾衰竭大鼠模型,手术组均在无菌条件下进行左肾上、下极切除,假手术组仅打开腹腔,正常组不作任何处理。右肾摘除1周后,把存活的手术组大鼠随机分为模型组、六味地黄汤组。六味组每天用六味地黄汤灌胃,模型组、假手术组和正常组以蒸馏水灌胃。连续灌胃8周后处死所有动物。于造模前、造模后1至9周,每2周称重一次。动物处死前收集尿液进行24h尿量及尿蛋白定量检测,收集血液检测BUN和CR水平,同时用HE染色、Masson染色观察左残肾组织形态学改变、用免疫组织化学、Western Blot、RT-PCR的方法分别检测大鼠留存肾组织中E-cadherin、α-SMA、FSP-1、TGF-β1BMP-7在蛋白水平和mRNA水平表达的差异,在细胞形态和分子生物水平的不同表达。
结果：①与正常组比较：模型组体重随喂养时间延长缓慢增加,但增长速度明显迟后,差异具有统计学意义(P<0.01)；24h尿量及尿蛋白定量均明显增高(P<0.01)；肾功能指标BUN、Cr均升高(P<0.01)；留存肾肉眼改变为质地硬韧,被膜不易剥离,切面肾皮质变薄,镜下改变为被膜纤维增厚,大部分肾小球萎缩、纤维化,肾小囊狭窄,少部分肾小球肥大,大部分肾小管上皮细胞萎缩、脱落,部分管腔不规则、扩张,管内存在大量蛋白质,肾间质有大量纤维结缔组织增生,出现明显的肾纤维化；模型组在蛋白水平和mRNA水平,上皮细胞标志物E-cadherin表达量明显下调,肌成纤维细胞标志物α-SMA、FSP-1表达量均明显上调,以上组间的差异均具有显著统计学意义(P<0.01),出现EMT现象,而TGF-β1表达水平上调,BMP-7表达水平下调,差异具有统计学意义(P<0.01)；②经六味地黄汤治疗8周后,与模型组比较：六味组大鼠体重增加明显,24h尿量及尿蛋白定量降低,BUN降低,以上组间差异均具有统计学意义(P<0.05),肾间质纤维化程度减轻,在蛋白水平和mRNA水平,E-cadherin表达量上调,a-SMA. FSP-1表达量均下调,EMT现象减轻,而TGF-β1表达水平下调,BMP-7表达水平上调,以上组间的差异具有统计学意义(P<0.01)。以上所有实验结果中,假手术组与正常组比较,差异无统计学意义(P>0.05)。
结论：①成功复制大鼠5/6肾切除致慢性肾衰竭模型；②证实大鼠5/6肾切除致慢性肾衰竭模型留存肾中存在EMT现象；③大鼠5/6肾切除致慢性肾衰竭模型留存肾中的EMT可能与TGF-β1表达水平上调,BMP-7表达水平下调有关；④六味地黄汤可减轻留存肾组织病理变化,延缓肾间质纤维化；⑤六味地黄汤可抑制EMT；⑥六味地黄汤可能通过下调TGF-β1表达水平,上调BMP-7表达水平,达到抑制EMT,抗肾间质纤维化的疗效机制。
Obiective:to research5/6nephrectomy chronic renal failure rats renal epithelial cells EMT to renal fibrosis mechanism, and explore the efficacy mechanism of Liuwei Dihuang decoction against renal fibrosis.
Methods:Healthy male Sprapue-Demey rats were randomly divided into normal group, sham operation group and operation group. Experimental rats after adaptive feeding for a week.Copy the5/6nephrectomy rat model of chronic renal failure. All operations were carried out under sterile conditions, the surgical group completed two operations, the first time the left kidney, the lower pole resection in1/3, a week after the completion of the second right kidney removal surgery, the sham operation group, only to open the abdominal cavity,The normal group without any treatment.One week after the removal of the right kidney, the survival of operated rats were randomly divided into model group, Liuwei Dihuang decoction group.The Liuwei group every day with Liuwei Dihuang decoction gavage, model group, sham group and normal group to distilled water. All animals were sacrificed after8weeks intragastrically. Prior to modeling, modeling after1-9weeks, weighing every two weeks. Before the animals were killed to collect blood to test BUN and CR levels, HE staining, Masson staining observed morphological changes of the left remnant kidney. Immunohistochemistry, Western blot, RT-PCR methods were used to detect E-cadherin, α-SMA, FSP-1, TGF-β1, BMP-7expression differences of the rat left remnant kidney at the protein and mRNA levels,in cell morphology and molecular biology level of differential expression.
Results:①Compared with normal group:model group, body weight slowly increased with the feeding times are extended, but the growth rate was significantly later, the difference was statistically significant (P<0.01);24h urine volume and urinary protein were significantly higher (P<0.01);Renal function, BUN, Cr were significantly increased (P<0.01); Retained renal naked eye to change as the texture is hard and tough, capsule difficult to peel, cut renal cortical thinning. Microscopic change capsule thickening fibers, most of the glomerular atrophy, fibrosis, and renal capsule narrow, a small number of glomerular hypertrophy, the majority of renal tubular epithelial cell atrophy, off, part of the lumen irregular expansion, there are a lot of protein in tube; renal interstitial fibrous connective tissue hyperplasia, apparent renal fibrosis; model group in the protein and mRNA levels, the epithelial cell marker E-cadherin expression level was significantly down-regulated and the muscle fiber cell marker α-SMA and FSP-1expression were significantly up-regulated, the difference between the above group were significant statistically significancet (P<0.01), EMT phenomenon appears, and TGF-β1expression levels increased, BMP-7expression levels lowered, the difference was statistically significance (P<0.01);②Compared with model group after8weeks Liuwei Dihuang decoction treatment:Liuwei group of rats body weight increased significantly,24h urine volume and urinary protein were lower,BUN was lower, the difference between the above groups were statistically significant (P<0.01), renal interstitial fibrosis to reduce, in the protein and mRNA levels, E-cadherin expression was up, α-SMA, FSP-1expression were down, EMT phenomena reduced, TGF-β1expression down-regulated, the expression of BMP-7level raised,above differences between the groups was statistically significant (P <0.01). All of the above experimental results, the sham operation group compared with normal group. was no significant difference (P>0.05).
Conelusion:①successfully copied5/6nephrectomy induced rat model of chronic renal failure;②confirmed EMT phenomenon in the rat remnant kidney of5/6nephrectomy-induced chronic renal failure model;③rat remnant kidney EMT in chronic renal failure model caused by5/6nephrectomy may be associated with TGF-β1upregulation and BMP-7downregulation in expression levels; the④Liuwei Dihuang decoction reduce the remnant renal pathological changes, and renal interstitial fibrosis;⑤The Liuwei Dihuang decoction inhibit the EMT;⑥The efficacy mechanism of Liuwei Dihuang decoction inhibiting the EMT and antagonising renal interstitial fibrosis may be by down-regulating TGF-β1and up-regulating BMP-7expression levels.
方法：将健康雄性Sprapue-Demey大鼠随机分成正常组、假手术组、手术组。实验大鼠适应性喂养一周,采用5/6肾切除法复制慢性肾衰竭大鼠模型,手术组均在无菌条件下进行左肾上、下极切除,假手术组仅打开腹腔,正常组不作任何处理。右肾摘除1周后,把存活的手术组大鼠随机分为模型组、六味地黄汤组。六味组每天用六味地黄汤灌胃,模型组、假手术组和正常组以蒸馏水灌胃。连续灌胃8周后处死所有动物。于造模前、造模后1至9周,每2周称重一次。动物处死前收集尿液进行24h尿量及尿蛋白定量检测,收集血液检测BUN和CR水平,同时用HE染色、Masson染色观察左残肾组织形态学改变、用免疫组织化学、Western Blot、RT-PCR的方法分别检测大鼠留存肾组织中E-cadherin、α-SMA、FSP-1、TGF-β1BMP-7在蛋白水平和mRNA水平表达的差异,在细胞形态和分子生物水平的不同表达。
结果：①与正常组比较：模型组体重随喂养时间延长缓慢增加,但增长速度明显迟后,差异具有统计学意义(P<0.01)；24h尿量及尿蛋白定量均明显增高(P<0.01)；肾功能指标BUN、Cr均升高(P<0.01)；留存肾肉眼改变为质地硬韧,被膜不易剥离,切面肾皮质变薄,镜下改变为被膜纤维增厚,大部分肾小球萎缩、纤维化,肾小囊狭窄,少部分肾小球肥大,大部分肾小管上皮细胞萎缩、脱落,部分管腔不规则、扩张,管内存在大量蛋白质,肾间质有大量纤维结缔组织增生,出现明显的肾纤维化；模型组在蛋白水平和mRNA水平,上皮细胞标志物E-cadherin表达量明显下调,肌成纤维细胞标志物α-SMA、FSP-1表达量均明显上调,以上组间的差异均具有显著统计学意义(P<0.01),出现EMT现象,而TGF-β1表达水平上调,BMP-7表达水平下调,差异具有统计学意义(P<0.01)；②经六味地黄汤治疗8周后,与模型组比较：六味组大鼠体重增加明显,24h尿量及尿蛋白定量降低,BUN降低,以上组间差异均具有统计学意义(P<0.05),肾间质纤维化程度减轻,在蛋白水平和mRNA水平,E-cadherin表达量上调,a-SMA. FSP-1表达量均下调,EMT现象减轻,而TGF-β1表达水平下调,BMP-7表达水平上调,以上组间的差异具有统计学意义(P<0.01)。以上所有实验结果中,假手术组与正常组比较,差异无统计学意义(P>0.05)。
结论：①成功复制大鼠5/6肾切除致慢性肾衰竭模型；②证实大鼠5/6肾切除致慢性肾衰竭模型留存肾中存在EMT现象；③大鼠5/6肾切除致慢性肾衰竭模型留存肾中的EMT可能与TGF-β1表达水平上调,BMP-7表达水平下调有关；④六味地黄汤可减轻留存肾组织病理变化,延缓肾间质纤维化；⑤六味地黄汤可抑制EMT；⑥六味地黄汤可能通过下调TGF-β1表达水平,上调BMP-7表达水平,达到抑制EMT,抗肾间质纤维化的疗效机制。
Obiective:to research5/6nephrectomy chronic renal failure rats renal epithelial cells EMT to renal fibrosis mechanism, and explore the efficacy mechanism of Liuwei Dihuang decoction against renal fibrosis.
Methods:Healthy male Sprapue-Demey rats were randomly divided into normal group, sham operation group and operation group. Experimental rats after adaptive feeding for a week.Copy the5/6nephrectomy rat model of chronic renal failure. All operations were carried out under sterile conditions, the surgical group completed two operations, the first time the left kidney, the lower pole resection in1/3, a week after the completion of the second right kidney removal surgery, the sham operation group, only to open the abdominal cavity,The normal group without any treatment.One week after the removal of the right kidney, the survival of operated rats were randomly divided into model group, Liuwei Dihuang decoction group.The Liuwei group every day with Liuwei Dihuang decoction gavage, model group, sham group and normal group to distilled water. All animals were sacrificed after8weeks intragastrically. Prior to modeling, modeling after1-9weeks, weighing every two weeks. Before the animals were killed to collect blood to test BUN and CR levels, HE staining, Masson staining observed morphological changes of the left remnant kidney. Immunohistochemistry, Western blot, RT-PCR methods were used to detect E-cadherin, α-SMA, FSP-1, TGF-β1, BMP-7expression differences of the rat left remnant kidney at the protein and mRNA levels,in cell morphology and molecular biology level of differential expression.
Results:①Compared with normal group:model group, body weight slowly increased with the feeding times are extended, but the growth rate was significantly later, the difference was statistically significant (P<0.01);24h urine volume and urinary protein were significantly higher (P<0.01);Renal function, BUN, Cr were significantly increased (P<0.01); Retained renal naked eye to change as the texture is hard and tough, capsule difficult to peel, cut renal cortical thinning. Microscopic change capsule thickening fibers, most of the glomerular atrophy, fibrosis, and renal capsule narrow, a small number of glomerular hypertrophy, the majority of renal tubular epithelial cell atrophy, off, part of the lumen irregular expansion, there are a lot of protein in tube; renal interstitial fibrous connective tissue hyperplasia, apparent renal fibrosis; model group in the protein and mRNA levels, the epithelial cell marker E-cadherin expression level was significantly down-regulated and the muscle fiber cell marker α-SMA and FSP-1expression were significantly up-regulated, the difference between the above group were significant statistically significancet (P<0.01), EMT phenomenon appears, and TGF-β1expression levels increased, BMP-7expression levels lowered, the difference was statistically significance (P<0.01);②Compared with model group after8weeks Liuwei Dihuang decoction treatment:Liuwei group of rats body weight increased significantly,24h urine volume and urinary protein were lower,BUN was lower, the difference between the above groups were statistically significant (P<0.01), renal interstitial fibrosis to reduce, in the protein and mRNA levels, E-cadherin expression was up, α-SMA, FSP-1expression were down, EMT phenomena reduced, TGF-β1expression down-regulated, the expression of BMP-7level raised,above differences between the groups was statistically significant (P <0.01). All of the above experimental results, the sham operation group compared with normal group. was no significant difference (P>0.05).
Conelusion:①successfully copied5/6nephrectomy induced rat model of chronic renal failure;②confirmed EMT phenomenon in the rat remnant kidney of5/6nephrectomy-induced chronic renal failure model;③rat remnant kidney EMT in chronic renal failure model caused by5/6nephrectomy may be associated with TGF-β1upregulation and BMP-7downregulation in expression levels; the④Liuwei Dihuang decoction reduce the remnant renal pathological changes, and renal interstitial fibrosis;⑤The Liuwei Dihuang decoction inhibit the EMT;⑥The efficacy mechanism of Liuwei Dihuang decoction inhibiting the EMT and antagonising renal interstitial fibrosis may be by down-regulating TGF-β1and up-regulating BMP-7expression levels.
引文
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