芪卫颗粒治疗DN临床观察及调节PEDF/USF_2表达对DN肾纤维化的干预机制研究
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摘要
本论文分为文献研究、临床观察、实验研究三部分。
文献研究介绍了近年来国内外对糖尿病肾病(DN)发病机制研究的主要观点、进展情况和发展趋势,以及中医对DN病因病机、辨证论治和实验研究等方面的进展情况,初步探讨了目前研究尚待解决的问题
临床观察目的：观察芪卫颗粒防治糖尿病肾病的临床疗效。方法：将70例证属气阴两虚、肾络瘀滞的糖尿病肾病Ⅲ期及Ⅳ期患者随机分为缬沙坦组和芪卫颗粒组,缬沙坦组采用基础治疗加缬沙坦口服,芪卫颗粒组采用基础治疗加芪卫颗粒口服,疗程为3个月,观察实验前后两组患者的中医临床症状、尿蛋白、早期血清标志物TGF-β1、CRP变化情况。结果：与缬沙坦组比较,芪卫颗粒组患者临床症状明显减轻(P<0.05),尿蛋白、血清TGF-β1、CRP水平明显降低(P<0.05)；两组综合疗效比较,芪卫颗粒组总有效率为87.9%,缬沙坦组总有效率为66.7%,芪卫颗粒组优于缬沙坦组,(P<0.05)；整个治疗阶段未见不良反应。结论：芪卫颗粒可明显改善DN患者的临床症状,减少尿白蛋白排泄,抑制DN机体微炎症状态、下调致纤维化因子表达水平,临床观察未见不良反应。
实验研究目的：观察芪卫颗粒调节PEDF/USF2表达对DN肾纤维化的干预作用。方法：将SPF级12周龄雄性自发性2型糖尿病动物模型KK-Ay小鼠60只按血糖值随机分为模型组,芪卫颗粒组,缬沙坦组,并选20只C57BL/6J小鼠为正常对照组。连续给药12周,实验结束时麻醉小鼠后取血并处死动物,取肾脏,检测各组血糖、糖化血红蛋白(HbAlc)、尿白蛋白排泄率(UAER)、尿微量白蛋白／尿肌酐比率(ACR)、肾重／体重(KW/BW)等指标；用光镜和电镜观察肾组织的结构变化,Masson染色观察肾脏纤维化程度,计算肾小球硬化指数。RT-PCR检测肾组织中PEDF、USF2、TGF-β1的mRNA表达；western blot检测肾组织中PEDF、USF2、TGF-β1、CTGF、ILK、MMP-9、TIMP-1的蛋白表达,免疫组化染色检测TGF-β1、Ⅳ型胶原、FN、LN在肾组织中的表达情况。
结果：实验一：与正常对照组比较,模型组肾小球面积增大、系膜区基质增多、系膜区面积/毛细血管襻面积增加、基底膜明显增厚、硬化指数(GSI)明显升高,尿蛋白明显增加(P<0.05)。经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组组织病理可见肾小球硬化和间质纤维化程度明显减轻,生化检验和图形半定量分析结果显示24hUAER、 ACR、KW/BW、MRA/CCA、GA、GBM、GSI等指标均明显降低(p<0.05)。实验二：与正常对照组比较,模型组肾组织中USF2、TGF-β1的mRNA和蛋白表达明显升高,PEDF的mRNA和蛋白表达明显降低；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组PEDF的mRNA和蛋白表达明显上调,USF2、TGF-β1表达显著下降(p<0.05)；芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)；相关性分析结果显示,PEDF与TGF-β1之间相互呈负线性相关,USF2和TGF-β1表达呈正相关。免疫组化染色显示,Ⅳ型胶原、FN、LN表达主要分布于肾小球基膜、系膜区和肾小管上皮细胞；与正常对照组比较,模型组Ⅳ型胶原、FN.LN表达明显增多(P<0.05)；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组Ⅳ型胶原、FN.LN蛋白表达明显降低(p<0.05)。芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)。实验三：与正常对照组比较,模型组KK-Ay小鼠肾脏TGF-β1及CTGF、ILK、TDMP-1表达明显增加,同时MMP-9表达明显下降,MMP-9/TIMP-1比例失衡；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组TGF-β1及CTGF、ILK、TIMP-1蛋白表达明显降低,MMP-9明显增加(p<0.05)；芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)。相关分析显示,TGF-β1与CTGF、ILK、TIMP-1表达呈正线性相关,与MMP-9表达呈负线性相关。结论：1、KK-Ay小鼠在实验过程中出现典型的DN肾脏病理改变和肾功能损害,是研究DN的理想动物模型。芪卫颗粒能减轻DN肾脏病理损害,减少尿蛋白排泄,改善肾功能。2、KK-Ay小鼠DN肾组织PEDF表达下降、USF2表达增加,使TGF-β1过表达,进而导致CTGF.ILK过表达,以及MMP-9/TIMP-1比例失衡,从而引起ECM合成增加、降解减少,ECM积聚渐至肾纤维化。3、芪卫颗粒通过刺激KK-Ay小鼠DN肾脏PEDF表达、抑制USF2表达而下调TGF-β1表达,进而下调CTGF、ILK过表达,纠正MMP-9/TIMP-1失衡,使ECM合成减少、降解增加,从而减轻ECM积聚,阻止或延缓肾纤维化病情进展。
This paper contains three parts including documental research, clinical observation and experimental research.
Documental Research We introduced the main ideas, advances and trend in the pathologic mechanism of diabetic nephropathy (DN) at home and abroad in recent years We also reviewed the advances in the etiology, pathogenesis, syndrome differentiation and treatment, experimental research of DN in TCM, and preliminarily discussed the unresolved problems at present.
Clinical Observation Objective:To observe the clinical efficacy of Qi-wei granules on the prevention and treatment of diabetic nephropathy. Methods:70diabetic nephropathy phase Ⅲ and Ⅳ patients with deficiency of both qi and yin, kidney collateral stasis were randomly divided into the control group being given valsartan orally and the therapy group being given Qi-wei granules orally, both groups were also given basic treatment, lasting for3months as a course of treatment. The changes of TCM clinical symptoms, proteinuria, TGF-β1, CRP (early serum markers) were observed on both groups before and after the experiment. Results: Significantly improved clinical symptoms (P<0.05) and obviously declined proteinuria,TGF-βi, CRP (P<0.05) were seen in the therapy group as compared with the control group; the comparison of the comprehensive therapeutic effect between two groups revealed that the total efficient rate of the therapy group was superior (87.9%) to that of the control group(66.7%)(P<0.05); there were no adverse reactions during the entire period treatment. Conclusion:Qi-wei granules can significantly improve the clinical symptoms of DN patients, reduce proteinuria, inhibit microinflammatory state, down-regulate the expression level of causative factors involved in renal fibrosis. There were no adverse reactions during the clinical observations.
Experimental Research Objective:To observe the interventional effect of Qi-wei granules regulating PEDF/USF2expression on DN renal fibrosis. Methods:60SPF grade12-week-old male KK-Ay mice with spontaneous type2diabetes were randomly divided into three groups:model group, Qi-wei granules group and valsartan group based the blood glucose level.20C57BL/6J mice were chosen as the normal control group. Being continuously administrated for12weeks, the mice were anesthetized and their blood was collected at the end of experiment. After that, the mice were sacrificed, their kidneys were removed, and then their blood sugar, HbA1c, UAER, ACR, KW/BW,etc. were examined.The structural changes in renal ti ssues were observed by light microscopy and electronic mi aoscopy. M asson staining was applied to observe the degree of renal fibrosis and cal cul ate glomerular sclerosis index. The mRNA expression of PEDF, USF2, TGF-β1in renal tissue was detected with RT-PCR. Western blot was used to detect the protein expression of PEDF, USF2, TGF-β1, CTGF, ILK, MMP-9, TIM P-1in renal tissue and Immunohistochemical staining was used to detect the expressi on of TGF-β1, Col I agen Type Ⅳ, FN and LN in renal tissue.
Results:Experiment1:Glomerular area(GI), extracellular matix of mesangial area, MRA/CCA, glomerular basement membrane(GBM), glomerulosclerosisindex (GSI), proteinuria in the model group increased markedly as compared with the normal control group (P<0.05). After treatment, the extent of glomerulosclerosis(FSGS) and renal interstitial fibrosis(RIF) was attenuated significantly in Qi-wei granules group and valsartan group as compared with the model group. The results of biochemical tests and semi-quantitative image analysis showed that there was a significant reduction of24hU A ER, ACR, KW/BW, MRA/CCA, GA, GBM, GSI,etc.(p<0.05). Experiment2:Messenger RNA (mRNA) and protein expression of USF2, TGF-β1increased markedly, mRNA and protein expression of PEDF decreased significantly in the model group as compared with the normal control group. After treatment, mRNA and protein expression of PEDF up-regulated, mRNA and protein expression of USF2, TGF-β1down-regulated in Qi-wei granules group and valsartan group as compared with the model group; there were no obvious differences between Qi-wei granules group and valsartan group (p>0.05); correlation analysis results showed that there was a negativelinear correlation between PEDF and TGF-β1expression, a positive linear correlation between USF2and TGF-β1.Immunohistochemical staining showed that the expressi on of Col I agen Ty pe IV, FN, L N was mainly di stri buted in the glomerul ar basement membrane, mesangial area and the renal tubular epithelial cells; the expression of Col I agen Type IV, FN, LN increased markedly in the model group as compared with the normal control group.(P<0.05); after treatment, the expression of Collagen Type Ⅳ, FN, LN declined markedly in Qi-wei granules group and val sartan group as compared with the model group; there were no obvious differences between Qi-wei granules group and valsartan group (p>0.05).Experiment3:The expression of TGF-β1, CTGF, ILK, TIM P-1increased markedly, MMP-9expressi on decreased significantly, MMP-9/TIMP-1was imbalanced in the model group as compared with the normal control group; after treatment, TGF-β1, CTGF, ILK,TIMP-1expression decreased markedly and MMP-9expression increased significantly in Qi-wei granules group and valsartan group as compared with the model group. There were no obvious differences between Qi-wei granules group and valsartan group(p>0.05).Correlation analysis results showed that there was a positive linear correlation between TGF-β1and CTGF、ILK、TIMP-1expression, a negative linear correlation between TGF-β1 and MM P-9expression. Conclusion:1. KK-Ay mice with DN showing typical renal pathological changes and impaired renal function in the experimental procedure, is an ideal animal model to research DN. Qi-wei granules can alleviate renal pathological changes, reduce urinary protein excretion, improve renal function in DN mice.2. Down-regulated expression of PEDF and up-regulated expression of USF2in the renal tissue of KK-Ay DN mice caused TGF-β1overexpression, and then CTGF, ILK overexpression and MM P-9/TIMP-1imbalance, thereby leading to increased ECM synthesis and decreased ECM degradation. The accumulation of ECM gradually resulted in renal fibrosis.3. Qi-wei granules inhibited TGF-β1expression by up-regulating PEDF expression and down-regulating USF2expression in the renal tissue of KK-Ay DN mice, and then inhibited CTGF, ILK overexpression, corrected MMP-9/TIMP-1imbalance, thereby leading to decreased ECM synthesis and increased ECM degradation. The progression of renal fibrosis was prevented or slowed as the result of reduced ECM accumulation.
文献研究介绍了近年来国内外对糖尿病肾病(DN)发病机制研究的主要观点、进展情况和发展趋势,以及中医对DN病因病机、辨证论治和实验研究等方面的进展情况,初步探讨了目前研究尚待解决的问题
临床观察目的：观察芪卫颗粒防治糖尿病肾病的临床疗效。方法：将70例证属气阴两虚、肾络瘀滞的糖尿病肾病Ⅲ期及Ⅳ期患者随机分为缬沙坦组和芪卫颗粒组,缬沙坦组采用基础治疗加缬沙坦口服,芪卫颗粒组采用基础治疗加芪卫颗粒口服,疗程为3个月,观察实验前后两组患者的中医临床症状、尿蛋白、早期血清标志物TGF-β1、CRP变化情况。结果：与缬沙坦组比较,芪卫颗粒组患者临床症状明显减轻(P<0.05),尿蛋白、血清TGF-β1、CRP水平明显降低(P<0.05)；两组综合疗效比较,芪卫颗粒组总有效率为87.9%,缬沙坦组总有效率为66.7%,芪卫颗粒组优于缬沙坦组,(P<0.05)；整个治疗阶段未见不良反应。结论：芪卫颗粒可明显改善DN患者的临床症状,减少尿白蛋白排泄,抑制DN机体微炎症状态、下调致纤维化因子表达水平,临床观察未见不良反应。
实验研究目的：观察芪卫颗粒调节PEDF/USF2表达对DN肾纤维化的干预作用。方法：将SPF级12周龄雄性自发性2型糖尿病动物模型KK-Ay小鼠60只按血糖值随机分为模型组,芪卫颗粒组,缬沙坦组,并选20只C57BL/6J小鼠为正常对照组。连续给药12周,实验结束时麻醉小鼠后取血并处死动物,取肾脏,检测各组血糖、糖化血红蛋白(HbAlc)、尿白蛋白排泄率(UAER)、尿微量白蛋白／尿肌酐比率(ACR)、肾重／体重(KW/BW)等指标；用光镜和电镜观察肾组织的结构变化,Masson染色观察肾脏纤维化程度,计算肾小球硬化指数。RT-PCR检测肾组织中PEDF、USF2、TGF-β1的mRNA表达；western blot检测肾组织中PEDF、USF2、TGF-β1、CTGF、ILK、MMP-9、TIMP-1的蛋白表达,免疫组化染色检测TGF-β1、Ⅳ型胶原、FN、LN在肾组织中的表达情况。
结果：实验一：与正常对照组比较,模型组肾小球面积增大、系膜区基质增多、系膜区面积/毛细血管襻面积增加、基底膜明显增厚、硬化指数(GSI)明显升高,尿蛋白明显增加(P<0.05)。经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组组织病理可见肾小球硬化和间质纤维化程度明显减轻,生化检验和图形半定量分析结果显示24hUAER、 ACR、KW/BW、MRA/CCA、GA、GBM、GSI等指标均明显降低(p<0.05)。实验二：与正常对照组比较,模型组肾组织中USF2、TGF-β1的mRNA和蛋白表达明显升高,PEDF的mRNA和蛋白表达明显降低；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组PEDF的mRNA和蛋白表达明显上调,USF2、TGF-β1表达显著下降(p<0.05)；芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)；相关性分析结果显示,PEDF与TGF-β1之间相互呈负线性相关,USF2和TGF-β1表达呈正相关。免疫组化染色显示,Ⅳ型胶原、FN、LN表达主要分布于肾小球基膜、系膜区和肾小管上皮细胞；与正常对照组比较,模型组Ⅳ型胶原、FN.LN表达明显增多(P<0.05)；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组Ⅳ型胶原、FN.LN蛋白表达明显降低(p<0.05)。芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)。实验三：与正常对照组比较,模型组KK-Ay小鼠肾脏TGF-β1及CTGF、ILK、TDMP-1表达明显增加,同时MMP-9表达明显下降,MMP-9/TIMP-1比例失衡；经治疗后,与模型组比较,芪卫颗粒组和缬沙坦组TGF-β1及CTGF、ILK、TIMP-1蛋白表达明显降低,MMP-9明显增加(p<0.05)；芪卫颗粒组和缬沙坦组组间比较无明显差异(p>0.05)。相关分析显示,TGF-β1与CTGF、ILK、TIMP-1表达呈正线性相关,与MMP-9表达呈负线性相关。结论：1、KK-Ay小鼠在实验过程中出现典型的DN肾脏病理改变和肾功能损害,是研究DN的理想动物模型。芪卫颗粒能减轻DN肾脏病理损害,减少尿蛋白排泄,改善肾功能。2、KK-Ay小鼠DN肾组织PEDF表达下降、USF2表达增加,使TGF-β1过表达,进而导致CTGF.ILK过表达,以及MMP-9/TIMP-1比例失衡,从而引起ECM合成增加、降解减少,ECM积聚渐至肾纤维化。3、芪卫颗粒通过刺激KK-Ay小鼠DN肾脏PEDF表达、抑制USF2表达而下调TGF-β1表达,进而下调CTGF、ILK过表达,纠正MMP-9/TIMP-1失衡,使ECM合成减少、降解增加,从而减轻ECM积聚,阻止或延缓肾纤维化病情进展。
This paper contains three parts including documental research, clinical observation and experimental research.
Documental Research We introduced the main ideas, advances and trend in the pathologic mechanism of diabetic nephropathy (DN) at home and abroad in recent years We also reviewed the advances in the etiology, pathogenesis, syndrome differentiation and treatment, experimental research of DN in TCM, and preliminarily discussed the unresolved problems at present.
Clinical Observation Objective:To observe the clinical efficacy of Qi-wei granules on the prevention and treatment of diabetic nephropathy. Methods:70diabetic nephropathy phase Ⅲ and Ⅳ patients with deficiency of both qi and yin, kidney collateral stasis were randomly divided into the control group being given valsartan orally and the therapy group being given Qi-wei granules orally, both groups were also given basic treatment, lasting for3months as a course of treatment. The changes of TCM clinical symptoms, proteinuria, TGF-β1, CRP (early serum markers) were observed on both groups before and after the experiment. Results: Significantly improved clinical symptoms (P<0.05) and obviously declined proteinuria,TGF-βi, CRP (P<0.05) were seen in the therapy group as compared with the control group; the comparison of the comprehensive therapeutic effect between two groups revealed that the total efficient rate of the therapy group was superior (87.9%) to that of the control group(66.7%)(P<0.05); there were no adverse reactions during the entire period treatment. Conclusion:Qi-wei granules can significantly improve the clinical symptoms of DN patients, reduce proteinuria, inhibit microinflammatory state, down-regulate the expression level of causative factors involved in renal fibrosis. There were no adverse reactions during the clinical observations.
Experimental Research Objective:To observe the interventional effect of Qi-wei granules regulating PEDF/USF2expression on DN renal fibrosis. Methods:60SPF grade12-week-old male KK-Ay mice with spontaneous type2diabetes were randomly divided into three groups:model group, Qi-wei granules group and valsartan group based the blood glucose level.20C57BL/6J mice were chosen as the normal control group. Being continuously administrated for12weeks, the mice were anesthetized and their blood was collected at the end of experiment. After that, the mice were sacrificed, their kidneys were removed, and then their blood sugar, HbA1c, UAER, ACR, KW/BW,etc. were examined.The structural changes in renal ti ssues were observed by light microscopy and electronic mi aoscopy. M asson staining was applied to observe the degree of renal fibrosis and cal cul ate glomerular sclerosis index. The mRNA expression of PEDF, USF2, TGF-β1in renal tissue was detected with RT-PCR. Western blot was used to detect the protein expression of PEDF, USF2, TGF-β1, CTGF, ILK, MMP-9, TIM P-1in renal tissue and Immunohistochemical staining was used to detect the expressi on of TGF-β1, Col I agen Type Ⅳ, FN and LN in renal tissue.
Results:Experiment1:Glomerular area(GI), extracellular matix of mesangial area, MRA/CCA, glomerular basement membrane(GBM), glomerulosclerosisindex (GSI), proteinuria in the model group increased markedly as compared with the normal control group (P<0.05). After treatment, the extent of glomerulosclerosis(FSGS) and renal interstitial fibrosis(RIF) was attenuated significantly in Qi-wei granules group and valsartan group as compared with the model group. The results of biochemical tests and semi-quantitative image analysis showed that there was a significant reduction of24hU A ER, ACR, KW/BW, MRA/CCA, GA, GBM, GSI,etc.(p<0.05). Experiment2:Messenger RNA (mRNA) and protein expression of USF2, TGF-β1increased markedly, mRNA and protein expression of PEDF decreased significantly in the model group as compared with the normal control group. After treatment, mRNA and protein expression of PEDF up-regulated, mRNA and protein expression of USF2, TGF-β1down-regulated in Qi-wei granules group and valsartan group as compared with the model group; there were no obvious differences between Qi-wei granules group and valsartan group (p>0.05); correlation analysis results showed that there was a negativelinear correlation between PEDF and TGF-β1expression, a positive linear correlation between USF2and TGF-β1.Immunohistochemical staining showed that the expressi on of Col I agen Ty pe IV, FN, L N was mainly di stri buted in the glomerul ar basement membrane, mesangial area and the renal tubular epithelial cells; the expression of Col I agen Type IV, FN, LN increased markedly in the model group as compared with the normal control group.(P<0.05); after treatment, the expression of Collagen Type Ⅳ, FN, LN declined markedly in Qi-wei granules group and val sartan group as compared with the model group; there were no obvious differences between Qi-wei granules group and valsartan group (p>0.05).Experiment3:The expression of TGF-β1, CTGF, ILK, TIM P-1increased markedly, MMP-9expressi on decreased significantly, MMP-9/TIMP-1was imbalanced in the model group as compared with the normal control group; after treatment, TGF-β1, CTGF, ILK,TIMP-1expression decreased markedly and MMP-9expression increased significantly in Qi-wei granules group and valsartan group as compared with the model group. There were no obvious differences between Qi-wei granules group and valsartan group(p>0.05).Correlation analysis results showed that there was a positive linear correlation between TGF-β1and CTGF、ILK、TIMP-1expression, a negative linear correlation between TGF-β1 and MM P-9expression. Conclusion:1. KK-Ay mice with DN showing typical renal pathological changes and impaired renal function in the experimental procedure, is an ideal animal model to research DN. Qi-wei granules can alleviate renal pathological changes, reduce urinary protein excretion, improve renal function in DN mice.2. Down-regulated expression of PEDF and up-regulated expression of USF2in the renal tissue of KK-Ay DN mice caused TGF-β1overexpression, and then CTGF, ILK overexpression and MM P-9/TIMP-1imbalance, thereby leading to increased ECM synthesis and decreased ECM degradation. The accumulation of ECM gradually resulted in renal fibrosis.3. Qi-wei granules inhibited TGF-β1expression by up-regulating PEDF expression and down-regulating USF2expression in the renal tissue of KK-Ay DN mice, and then inhibited CTGF, ILK overexpression, corrected MMP-9/TIMP-1imbalance, thereby leading to decreased ECM synthesis and increased ECM degradation. The progression of renal fibrosis was prevented or slowed as the result of reduced ECM accumulation.
引文
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