肾安提取液对糖尿病肾病小鼠肾脏保护作用及TGF-β1表达与信号转导的影响
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摘要
本课题以成功建立糖尿病肾病(DN)小鼠为动物模型,从血、尿生化学、肾脏病理组织学、分子生物学等方面对肾安提取液进行研究,旨在探讨肾安提取液防治DN的作用及可能机制。
实验一,目的：建立DN小鼠动物模型。方法：以C57BL／6小鼠为研究对象,予以腹腔注射链脲佐菌素(STZ,150mg·kg-1),观察小鼠一般情况、血糖、尿蛋白、肾质量／体质量(KW/BW)、血尿素氮(BUN)、血肌酐(Scr)及肾组织光镜、透射电镜下的病理变化。结果：与正常对照组比较,模型组小鼠体重明显下降(P<0.01),第3天即开始血糖持续性升高(P<0.01),1周后出现蛋白尿,4周后BUN、Scr升高(P<0.01).KW/BW明显升高(P<0.01),光镜下显示,肾小球肥大,系膜区增宽,基质增多,肾小球硬化指数增加(P<0.05,P<0.01)；电镜下显示,足突增宽、扁平、融合,足细胞减少,肾小球基底膜(GBM)裸露,GBM明显增厚(P<0.05,P<0.01)。结论：提示腹腔注射STZ(150mg·kg-1)能成功诱导C57BL／6小鼠DN模型。
实验二,目的：探讨肾安提取液对DN小鼠生化指标的影响。方法：将C57BL／6小鼠随机分为正常对照组、模型组、厄贝沙坦组、肾安低、中、高剂量组(各9只),各药物干预组分别给予厄贝沙坦10mg/kg.肾安提取液(由黄芪甲苷、淫羊藿苷和1,8二羟基蒽醌组成)2.272mg/kg. 4.544mg/kg.9.088mg/kg灌胃,定期检测血糖、尿蛋白、BUN、Scr。结果：与正常对照组比较,其余各组小鼠血糖均明显升高(P<0.01),随着时间延长,各药物干预组血糖无降低,与模型组无差异(P>0.05)；与模型组比较,各药物干预组尿蛋白定量明显减少(P<0.01),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；第4周未,与模型组比较,各药物干预组BUN明显降低(P<0.05,P<0.01),肾安高剂量组及厄贝沙坦组Scr显著降低(P<0.05,P<0.01),肾安高剂量组BUN显著低于厄贝沙坦组(P<0.05),Scr两组间无显著性差异(P>0.05)。结论：肾安提取液能减少DN小鼠尿蛋白排出,降低BUN、Scr,对DN肾功能具有良好的保护作用,但无降血糖作用。
实验三,目的：探讨肾安提取液对DN小鼠肾脏组织形态学影响。方法：分组及给药方法同实验二；采用KW/BW、肾小球硬化指数、纤粘连蛋白(FN)半定量积分、GBM厚度等为观察指标。结果：肾安各剂量组KW/BW明显改善(P<0.05,P<0.01),肾安中、高剂量组与厄贝沙坦组无显著差异(P>0.05)；光镜下肾安各剂组肾组织病理变化较模型组明显减轻,肾小球硬化指数明显改善(P<0.05,P<0.01),肾安中、高剂量组肾小球硬化指数与厄贝沙坦组比较无显著差异(P>0.05)；肾安各剂量组FN表达呈不同程度减弱(P<0.05,P<0.01),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；电镜下肾安各剂量组超微结构明显改善,各组GBM增厚明显减轻(P<0.05,P<0.01),肾安中、高剂量组GBM厚度与厄贝沙坦组无显著差异(P>0.05)。结论：肾安提取液能抑制DN小鼠肾组织FN蛋白表达,改善肾小球肥大,减少ECM积聚,抑制GBM增厚,减轻足细胞损伤,延缓肾小球硬化。
实验四,目的：探讨肾安提取液对DN小鼠肾脏转录活化蛋白-1(AP-1)及TGF-β1mRNA及蛋白表达的影响。方法：肾组织标本取材于生化学研究部分,分组方法相同；采用免疫印迹法检测AP-1蛋白含量、实时荧光定量PCR检测TGF-β1mRNA表达及免疫组化检测TGF-β1蛋白含量。结果：肾安提取液各组AP-1(c-Jun亚基)蛋白显著低于模型组(P<0.01),肾安高剂量组与厄贝沙坦组AP-1(c-Jun亚基)蛋白表达无显著性差异(P>0.05)；肾安各剂量组TGF-β1mRNA表达及蛋白含量显著低于模型组(P<0.01),肾安高剂量组与厄贝沙坦组TGF-β1mRNA表达及蛋白含量无显著性差异(P>0.05)。结论：肾安提取液能明显抑制DN小鼠肾组织AP-1蛋白和TGF-β1表达。
实验五：目的：探讨肾安提取液对DN小鼠肾皮质p38丝裂原活化的蛋白激酶(MAPK)mRNA及磷酸化p38MAPK(p-p38MAPK)和Smad7蛋白表达的影响。方法：肾组织标本取材于生化学研究部分,分组方法相同；采用实时荧光定量PCR检测p38MAPK mRNA表达,免疫组化法半定量检测p-p38MAPK和Smad7蛋白含量。结果：肾安提取液各组肾皮质p38MAPK mRNA表达显著低于模型组(P<0.01,P<0.05),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；肾安提取液各组肾皮质p-p38MAPK蛋白相对含量显著低于模型组(P<0.01,P<0.05)；肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；肾安提取液各组肾皮质Smad7蛋白相对含量显著低于模型组(P<0.01)；肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)。结论：肾安提取液能抑制DN小鼠肾组织p38MAPK mRNA、p-p38MAPK及Smad7蛋白表达。
综上所述,肾安提取液能减少DN小鼠尿蛋白排出,改善DN肾功能,减轻DN小鼠肾组织病理变化,延缓肾小球硬化,对DN肾损害具有良好的保护作用。其作用机制可能与降低肾组织AP-1蛋白表达,抑制TGF-β1表达与信号转导,从而减少ECM积聚,抑制足细胞的凋亡等有关。
In this study, we have successfully established a mice model of diabetic nephropathy(DN). In order to explore the effects and possible mechanisms of Shenvan Extraction on DN, blood, urine biochemistry, renal histopathology and cytokines in transforming growth factor-β1 pathway are detected.
DN model was induced by intraperitoneal injection of streptozotoc(STZ) (150mg/kg) in C57BL/6 mice. The change of the general situation, blood glucose, urine protein, kidney weight/body weight (KW/BW), blood urea nitrogen (BUN), serum creatinine (Scr) and pathomorphology in kidney by light microscopy and transmission electron microscopy in mice were observed. The results showed that compared with the normal control group, model group body weight of mice decreased significantly (P<0.01), from the third day blood glucose continued to rise(P<0.01), after 1 week proteinuria appeared and after 4 weeks BUN, Scr increased (P< 0.01). In the model group KW/BW was significantly higher(P<0.01), by light microscope glomerular hypertrophy, widened Essential area and matrix increase were observed, as well as glomerular sclerosis index was increased (P<0.05, P<0.01); by electron microscopy foot process broadening, flat, integration, reduction of foot cells and exposed glomerular basement membrane (GBM) were showed, and the GBM was significantly thicker (P<0.05, P<0.01).
To explore the effects of Shen'an Extraction on DN mice blood sugar, urine protein, BUN and Scr. The C57BL/6 mice were randomly divided into normal control group, model group, irbesartan group, Shen'an low, middle and high-dose group. The intervention groups were respectively given the drug irbesartan 10mg/kg, mixture of Astragaloside, Icariin and 1,8-Dihydroxy anthraquinone(Shen'an Extraction) 2.272mg/kg,4.544mg/kg and 9.088mg/kg for 4 weeks by gavage. The results showed that the blood glucose in the other groups with persistent hyperglycemia, with no difference between them(P>0.05), is significantly higher than the normal control group(P<0.01). The urine protein in the drug intervention groups was significantly lower than the model group(P<0.01), and was no difference between Shen'an high-dose and irbesartan group (P>0.05). After 4 weeks, compared with the model group, the BUN in all drug intervention groups and Scr in Shen'an high-dose group and irbesartan group were significantly lower (P<0.05, P<0.01). The BUN in Shen'an high-dose group was lower than irbesartan group(P <0.05); Scr was no difference between them(P>0.05).
In the histological study of kidney, tissue samples are based on the biochemistry research components, grouped with the same way. The results showed that in each dose group with Shen'an Extraction KW/BW, glomerular sclerosis index, FN expression and GBM thickness were all significantly improved(P<0.05, P<0.01). FN expression was no difference between Shen'an high-dose group and irbesartan group (P>0.05), and the other indexes were no difference between Shen'an middle/high-dose group and irbesartan group (P>0.05), too. As the dose increased Shen'an Extraction, renal pathological was thus gradually alleviated.
In this study, DN mice kidney transcription activator protein-1(AP-1) (western blot), TGF-β1 mRNA(RT-PCR) and protein (Immunohistochemistry) was detected. The results showed that protein expression of AP-1 (c-Jun subunit) of kidney in each dose group with Shen'an Extraction was significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05); mRNA and protein expression of TGF-β1 of kidney in each dose group with Shen'an Extraction were significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05).
In the last part DN mice kidney p38 mitogen activated protein kinase(MAPK) mRNA (RT-PCR), phosphor-p38MAPK(p-p38MAPK) and Smad7 (Immunohistochemistry) expression was detected. The results showed that mRNA expression of p38MAPK of kidney in each dose group with Shen'an Extraction was significantly lower than model group(P< 0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05); protein expression of p-p38MAPK and Smad7 of kidney in each dose group with Shen'an Extraction were significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group (P>0.05).
In conclusion, Shen'an Extraction can reduce urinary protein, improve renal function, ameliorate renal pathological changes, delay the onset of glomerular sclerosis, and renal damage is protected in DN mice. The mechanism may be related to reduce the accumulation of ECM and inhibit foot cell apoptosis by reducing renal AP-1 protein expression, thereby inhibiting TGF-β1 expression and signal transduction.
实验一,目的：建立DN小鼠动物模型。方法：以C57BL／6小鼠为研究对象,予以腹腔注射链脲佐菌素(STZ,150mg·kg-1),观察小鼠一般情况、血糖、尿蛋白、肾质量／体质量(KW/BW)、血尿素氮(BUN)、血肌酐(Scr)及肾组织光镜、透射电镜下的病理变化。结果：与正常对照组比较,模型组小鼠体重明显下降(P<0.01),第3天即开始血糖持续性升高(P<0.01),1周后出现蛋白尿,4周后BUN、Scr升高(P<0.01).KW/BW明显升高(P<0.01),光镜下显示,肾小球肥大,系膜区增宽,基质增多,肾小球硬化指数增加(P<0.05,P<0.01)；电镜下显示,足突增宽、扁平、融合,足细胞减少,肾小球基底膜(GBM)裸露,GBM明显增厚(P<0.05,P<0.01)。结论：提示腹腔注射STZ(150mg·kg-1)能成功诱导C57BL／6小鼠DN模型。
实验二,目的：探讨肾安提取液对DN小鼠生化指标的影响。方法：将C57BL／6小鼠随机分为正常对照组、模型组、厄贝沙坦组、肾安低、中、高剂量组(各9只),各药物干预组分别给予厄贝沙坦10mg/kg.肾安提取液(由黄芪甲苷、淫羊藿苷和1,8二羟基蒽醌组成)2.272mg/kg. 4.544mg/kg.9.088mg/kg灌胃,定期检测血糖、尿蛋白、BUN、Scr。结果：与正常对照组比较,其余各组小鼠血糖均明显升高(P<0.01),随着时间延长,各药物干预组血糖无降低,与模型组无差异(P>0.05)；与模型组比较,各药物干预组尿蛋白定量明显减少(P<0.01),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；第4周未,与模型组比较,各药物干预组BUN明显降低(P<0.05,P<0.01),肾安高剂量组及厄贝沙坦组Scr显著降低(P<0.05,P<0.01),肾安高剂量组BUN显著低于厄贝沙坦组(P<0.05),Scr两组间无显著性差异(P>0.05)。结论：肾安提取液能减少DN小鼠尿蛋白排出,降低BUN、Scr,对DN肾功能具有良好的保护作用,但无降血糖作用。
实验三,目的：探讨肾安提取液对DN小鼠肾脏组织形态学影响。方法：分组及给药方法同实验二；采用KW/BW、肾小球硬化指数、纤粘连蛋白(FN)半定量积分、GBM厚度等为观察指标。结果：肾安各剂量组KW/BW明显改善(P<0.05,P<0.01),肾安中、高剂量组与厄贝沙坦组无显著差异(P>0.05)；光镜下肾安各剂组肾组织病理变化较模型组明显减轻,肾小球硬化指数明显改善(P<0.05,P<0.01),肾安中、高剂量组肾小球硬化指数与厄贝沙坦组比较无显著差异(P>0.05)；肾安各剂量组FN表达呈不同程度减弱(P<0.05,P<0.01),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；电镜下肾安各剂量组超微结构明显改善,各组GBM增厚明显减轻(P<0.05,P<0.01),肾安中、高剂量组GBM厚度与厄贝沙坦组无显著差异(P>0.05)。结论：肾安提取液能抑制DN小鼠肾组织FN蛋白表达,改善肾小球肥大,减少ECM积聚,抑制GBM增厚,减轻足细胞损伤,延缓肾小球硬化。
实验四,目的：探讨肾安提取液对DN小鼠肾脏转录活化蛋白-1(AP-1)及TGF-β1mRNA及蛋白表达的影响。方法：肾组织标本取材于生化学研究部分,分组方法相同；采用免疫印迹法检测AP-1蛋白含量、实时荧光定量PCR检测TGF-β1mRNA表达及免疫组化检测TGF-β1蛋白含量。结果：肾安提取液各组AP-1(c-Jun亚基)蛋白显著低于模型组(P<0.01),肾安高剂量组与厄贝沙坦组AP-1(c-Jun亚基)蛋白表达无显著性差异(P>0.05)；肾安各剂量组TGF-β1mRNA表达及蛋白含量显著低于模型组(P<0.01),肾安高剂量组与厄贝沙坦组TGF-β1mRNA表达及蛋白含量无显著性差异(P>0.05)。结论：肾安提取液能明显抑制DN小鼠肾组织AP-1蛋白和TGF-β1表达。
实验五：目的：探讨肾安提取液对DN小鼠肾皮质p38丝裂原活化的蛋白激酶(MAPK)mRNA及磷酸化p38MAPK(p-p38MAPK)和Smad7蛋白表达的影响。方法：肾组织标本取材于生化学研究部分,分组方法相同；采用实时荧光定量PCR检测p38MAPK mRNA表达,免疫组化法半定量检测p-p38MAPK和Smad7蛋白含量。结果：肾安提取液各组肾皮质p38MAPK mRNA表达显著低于模型组(P<0.01,P<0.05),肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；肾安提取液各组肾皮质p-p38MAPK蛋白相对含量显著低于模型组(P<0.01,P<0.05)；肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)；肾安提取液各组肾皮质Smad7蛋白相对含量显著低于模型组(P<0.01)；肾安高剂量组与厄贝沙坦组无显著性差异(P>0.05)。结论：肾安提取液能抑制DN小鼠肾组织p38MAPK mRNA、p-p38MAPK及Smad7蛋白表达。
综上所述,肾安提取液能减少DN小鼠尿蛋白排出,改善DN肾功能,减轻DN小鼠肾组织病理变化,延缓肾小球硬化,对DN肾损害具有良好的保护作用。其作用机制可能与降低肾组织AP-1蛋白表达,抑制TGF-β1表达与信号转导,从而减少ECM积聚,抑制足细胞的凋亡等有关。
In this study, we have successfully established a mice model of diabetic nephropathy(DN). In order to explore the effects and possible mechanisms of Shenvan Extraction on DN, blood, urine biochemistry, renal histopathology and cytokines in transforming growth factor-β1 pathway are detected.
DN model was induced by intraperitoneal injection of streptozotoc(STZ) (150mg/kg) in C57BL/6 mice. The change of the general situation, blood glucose, urine protein, kidney weight/body weight (KW/BW), blood urea nitrogen (BUN), serum creatinine (Scr) and pathomorphology in kidney by light microscopy and transmission electron microscopy in mice were observed. The results showed that compared with the normal control group, model group body weight of mice decreased significantly (P<0.01), from the third day blood glucose continued to rise(P<0.01), after 1 week proteinuria appeared and after 4 weeks BUN, Scr increased (P< 0.01). In the model group KW/BW was significantly higher(P<0.01), by light microscope glomerular hypertrophy, widened Essential area and matrix increase were observed, as well as glomerular sclerosis index was increased (P<0.05, P<0.01); by electron microscopy foot process broadening, flat, integration, reduction of foot cells and exposed glomerular basement membrane (GBM) were showed, and the GBM was significantly thicker (P<0.05, P<0.01).
To explore the effects of Shen'an Extraction on DN mice blood sugar, urine protein, BUN and Scr. The C57BL/6 mice were randomly divided into normal control group, model group, irbesartan group, Shen'an low, middle and high-dose group. The intervention groups were respectively given the drug irbesartan 10mg/kg, mixture of Astragaloside, Icariin and 1,8-Dihydroxy anthraquinone(Shen'an Extraction) 2.272mg/kg,4.544mg/kg and 9.088mg/kg for 4 weeks by gavage. The results showed that the blood glucose in the other groups with persistent hyperglycemia, with no difference between them(P>0.05), is significantly higher than the normal control group(P<0.01). The urine protein in the drug intervention groups was significantly lower than the model group(P<0.01), and was no difference between Shen'an high-dose and irbesartan group (P>0.05). After 4 weeks, compared with the model group, the BUN in all drug intervention groups and Scr in Shen'an high-dose group and irbesartan group were significantly lower (P<0.05, P<0.01). The BUN in Shen'an high-dose group was lower than irbesartan group(P <0.05); Scr was no difference between them(P>0.05).
In the histological study of kidney, tissue samples are based on the biochemistry research components, grouped with the same way. The results showed that in each dose group with Shen'an Extraction KW/BW, glomerular sclerosis index, FN expression and GBM thickness were all significantly improved(P<0.05, P<0.01). FN expression was no difference between Shen'an high-dose group and irbesartan group (P>0.05), and the other indexes were no difference between Shen'an middle/high-dose group and irbesartan group (P>0.05), too. As the dose increased Shen'an Extraction, renal pathological was thus gradually alleviated.
In this study, DN mice kidney transcription activator protein-1(AP-1) (western blot), TGF-β1 mRNA(RT-PCR) and protein (Immunohistochemistry) was detected. The results showed that protein expression of AP-1 (c-Jun subunit) of kidney in each dose group with Shen'an Extraction was significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05); mRNA and protein expression of TGF-β1 of kidney in each dose group with Shen'an Extraction were significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05).
In the last part DN mice kidney p38 mitogen activated protein kinase(MAPK) mRNA (RT-PCR), phosphor-p38MAPK(p-p38MAPK) and Smad7 (Immunohistochemistry) expression was detected. The results showed that mRNA expression of p38MAPK of kidney in each dose group with Shen'an Extraction was significantly lower than model group(P< 0.01), and no difference between Shen'an high-dose group and irbesartan group(P>0.05); protein expression of p-p38MAPK and Smad7 of kidney in each dose group with Shen'an Extraction were significantly lower than model group(P<0.01), and no difference between Shen'an high-dose group and irbesartan group (P>0.05).
In conclusion, Shen'an Extraction can reduce urinary protein, improve renal function, ameliorate renal pathological changes, delay the onset of glomerular sclerosis, and renal damage is protected in DN mice. The mechanism may be related to reduce the accumulation of ECM and inhibit foot cell apoptosis by reducing renal AP-1 protein expression, thereby inhibiting TGF-β1 expression and signal transduction.
引文
[1]叶任高主编.中西医结合肾脏病学.北京：人民出版社,2003,300-307.
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