榛花消肾胶囊干预实验性糖尿病大鼠足细胞转分化wnt/β-catenin通路的研究
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摘要
目的：糖尿病肾病（DN）是糖尿病常见而严重的微血管并发症，以蛋白尿，肾功能进行性恶化为主要特征，病理变化主要为肾小球滤过率改变，基底膜增厚，系膜细胞增宽，直至肾小球硬化，发展至肾功衰竭。其发病率之高，进展速度之快，严重威胁着人类的健康。
糖尿病肾病的发病机制多而复杂，近几年，从蛋白尿产生机制角度入手，对足细胞的研究成为热点。各种原因导致足细胞的损伤参与了蛋白尿的产生，而改善足细胞功能的药物成为治疗糖尿病肾病的关注点和创新点。目前对于糖尿病肾病蛋白尿的治疗，西医多以降糖药、ACEI/ARB类药、改善循环为主，发展至中晚期则直接采用透析疗法维持。而中药在治疗蛋白尿方面取得良好效果，具有西药无法比拟的优势。榛花消肾胶囊是导师常用的治疗糖尿病肾病蛋白尿的方剂，在临床患者中取得满意疗效，本次实验是应用榛花消肾胶囊干预实验性糖尿病大鼠，观察该中药对足细胞相关分子及转分化wnt/β-catenin通路的影响，进一步证明榛花消肾胶囊治疗糖尿病肾病蛋白尿的有效性。
方法：
1将Wistar大鼠高脂饲料喂养一个月后予链脲佐菌素（STZ）腹腔注射，复制糖尿病大鼠模型，将造模成功大鼠随机分成DM模型组，中药实验组，西药对照组，同时设立正常对照组。中药实验组予榛花消肾胶囊灌胃，西药对照组予罗格列酮合苯那普利做阳性对照。观察大鼠一般状态，检测血糖、血脂、肾功、尿量、尿微量白蛋白等变化。
2应用光学显微镜和透视电镜观察肾组织超微结构，观察榛花消肾胶囊对糖尿病大鼠肾脏病理组织结构的改变。
3采用免疫组化方法观察足细胞标志性分子nephrin、desmin、zo-1的蛋白表达；应用荧光定量PCR技术检测nephrin、desmin m RNA表达。
4采用免疫组化方法观察足细胞转分化wnt/β-catenin通路相关分子wnt-1、β-catenin、sail1蛋白表达；应用荧光定量PCR技术检测wnt-1、sail1m RNA表达。
结果：
1榛花消肾胶囊能够改善实验性DM大鼠的一般状态以及多饮、多食、多尿、消瘦的临床症状。
2榛花消肾胶囊对实验性DM大鼠具有一定的降血糖、降低甘油三酯和胆固醇的作用，改善糖脂代谢。
3榛花消肾胶囊能够抑制实验性DM大鼠早期肾脏肥大，减少尿微量白蛋白的排出，降低血肌酐和尿素氮，改善肾功能。
4榛花消肾胶囊具有改善实验性DM大鼠肾脏组织的病理形态，减轻肾小球基底膜增厚，细胞外基质的积聚，系膜增生，改善足细胞形态，从而减轻DM性肾小球硬化。
5榛花消肾胶囊具有抑制实验性DM大鼠肾组织nephrin、zo-1蛋白及m RNA的表达，增加desmin蛋白及m RNA的表达。
6榛花消肾胶囊具有抑制实验性DM大鼠肾组织转分化wnt/β-catenin通路中wnt-1、β-catenin、sail1蛋白及m RNA的表达。
结论：榛花消肾胶囊能够改善实验性DM大鼠一般状态以及多饮、多食、多尿、消瘦的症状；抑制早期肾脏肥大，减轻肾组织病理结构；具有降血糖、降低甘油三酯和胆固醇、减少尿微量白蛋白，降低血肌酐和尿素氮的作用。同时，榛花消肾胶囊亦能改善足细胞相关分子nephrin、zo-1、desmin表达，抑制足细胞转分化wnt/β-catenin信号转导通路分子wnt-1、β-catenin、sail1表达。说明榛花消肾胶囊是通过干预足细胞转分化wnt/β-catenin通路而发挥改善糖、脂代谢，减少尿蛋白，改善肾功的作用。
导师南征教授认为消渴肾病的病机关键是毒损肾络，邪伏膜原。创造性地将中医学毒损肾络、邪伏膜原理论与西医学糖尿病肾病发病机制，肾小球滤过膜-足细胞结构及功能联系在一起。榛花消肾胶囊在解毒通络、疏利膜原、益肾导邪的治疗大法指导下，通过干预足细胞转分化wnt/β-catenin通路而发挥治疗糖尿病肾病的作用。
Propose: Diabetic nephropathy (DN) is a common and serious diabetic complication ofblood vascular. The main features of DN are proteinuria and renal function changes.The mainpathological changes are glomerular filtration change, thickening of the basement membrane,mesangial cells widened, glomerular sclerosis, until the renal failure. Its high incidence andfast progress is a serious threat to human health.
The pathogenesis of diabetic nephropathy is more complex. In recent years, for the pointof view of the mechanism of proteinuria, podocyte has become a hot research. All factorsinjury podocyte will be involved in proteinuria, so the drug for improving podocyte functionbecomes hot spot and innovation in treatment of diabetic nephropathy. For the treatment ofdiabetic nephropathy proteinuria, Western medicine mainly adopt degraded blood glucosedrugs, ACEI/ARB drugs, improving circulatory drugs, until dialysis therapy whenintermediate stage or advanced stage. And traditional Chinese medicine in the treatment ofproteinuria has fine effective, which the western medicine can not be matched.ZhenHuaXiaoShen capsule my advisor commonly used is a prescription in the treatment ofdiabetic nephropathy proteinuria, which achieves satisfactory effect in clinical patients. Thisexperiment observes the influence of podocyte correlated molecules and podocyte EMT inwnt/β-catenin signal transduction pathway by ZhenHuaXiaoShen capsule interventionexperimental diabetic rats. And further evidence of ZhenHuaXiaoShen capsule for thetreatment of diabetic nephropathy proteinuria is effective.
Method:
1Wistar rats being feed with hypsi-lipoids feeder for a month has been intraperitonealinjected with streptozotocin (STZ) for making diabetic rat model. The successful DM rats arerandomly divided into DM model group, the experimental group with traditional Chinesemedicine, the control group with western medicine, and normal control group.ZhenHuaXiaoShen capsule has been used in the experimental group, while rosiglitazone andbenazepril has been used together in the control group. Observed rats the general state, testingthe blood glucose, blood lipids, renal function, urine output and urine micro albumin.
2Observed renal ultrastructure by optical microscope and perspective electronmicroscopy, and analyzed the renal organism pathological structure changes for ZhenHuaXiaoShen capsule intervention experimental diabetic rats.
3Observed the protein expression of podocyte signal molecule，like nephrin, desmin,zo-1by immunohistochemical method, and m RNA expression of nephrin, desmin byfluorescent quantitative PCR methods.
4Observed the protein expression of podocyte EMT related molecules, like wnt-1、β-catenin、snail1in wnt/β-catenin signal transduction pathway by immunohistochemicalmethod, and m RNA expression of wnt-1, snail1by fluorescent quantitative PCR.
Result:
1ZhenHuaXiaoShen capsules can improve the experimental DM rats the general stateand clinical symptoms, such as polydipsia, polyphagia, polyuria and athrepsy.
2ZhenHuaXiaoShen capsules can degrade the experimental DM rats blood glucose,triglyceride, cholesterol in a certain degree, and improve glycometabolism and lipidmetabolism.
3ZhenHuaXiaoShen capsule can inhibit the experimental DM rats the early renalhypertrophy, reduce urinary albumin discharge, degrade serum creatinine and blood ureanitrogen, improve renal function.
4ZhenHuaXiaoShen capsules improve the experimental DM rats nephridial tissuepathology, reduce the thickening of the glomerular basement membrane, extracellular matrixaccumulation, mesangial hyperplasy, improve podocyte morphous, thereby reducing DMglomerulosclerosis.
5ZhenHuaXiaoShen capsule can inhibit the experimental DM rats nephridial tissueprotein and m RNA expression of nephrin and zo-1, increase protein and m RNA expressionof desmin.
6ZhenHuaXiaoShen capsule can inhibit the experimental DM rats nephridial tissueprotein and m RNA expression of wnt-1, β-catenin and sail1in wnt/β-catenin signaltransduction pathway.
Conclusion：
ZhenHuaXiaoShen capsules can improve the experimental DM rats the general state andclinical symptoms of polydipsia, polyphagia, polyuria and athrepsy; inhibit the early renalhypertrophy and relieve the renal pathological structure; degrade blood glucose, triglyceride,cholesterol, reduce urinary albumin discharge, degrade serum creatinine and blood urea nitrogen. ZhenHuaXiaoShen capsules can also improve podocyte correlated proteinexpression of nephrin, zo-1and desmin, inhibit the expression of wnt-1, β-catenin and sail1in podocyte EMT in wnt/β-catenin signal transduction pathway. Therefore,ZhenHuaXiaoShen capsules can improve glycometabolism and lipid metabolism, reduceurine protein, and protect renal function by the way of intervention in podocyte EMT in wnt/β-catenin signal transduction pathway.
My advisor NanZheng professor considers that the pathogenesis key of diabeticnephropathy is poison damaged renal meridian and hidden in pleurodiaphragmatic spaces.Creatively associate two theory of the traditional Chinese medicine theory of poison damagedrenal meridian and hidden in pleurodiaphragmatic spaces and western medicine diabeticnephropathy pathogenesis, glomerular filtration membrane-structure and function ofpodocytes together. ZhenHuaXiaoShen capsule could treat diabetic nephropathy in the way ofdetoxification-deoppilation meridian and pleurodiaphragmatic spaces-tonifying kidney-eliminate pathogen by intervention podocyte EMT in wnt/β-catenin signal transductionpathway.
糖尿病肾病的发病机制多而复杂，近几年，从蛋白尿产生机制角度入手，对足细胞的研究成为热点。各种原因导致足细胞的损伤参与了蛋白尿的产生，而改善足细胞功能的药物成为治疗糖尿病肾病的关注点和创新点。目前对于糖尿病肾病蛋白尿的治疗，西医多以降糖药、ACEI/ARB类药、改善循环为主，发展至中晚期则直接采用透析疗法维持。而中药在治疗蛋白尿方面取得良好效果，具有西药无法比拟的优势。榛花消肾胶囊是导师常用的治疗糖尿病肾病蛋白尿的方剂，在临床患者中取得满意疗效，本次实验是应用榛花消肾胶囊干预实验性糖尿病大鼠，观察该中药对足细胞相关分子及转分化wnt/β-catenin通路的影响，进一步证明榛花消肾胶囊治疗糖尿病肾病蛋白尿的有效性。
方法：
1将Wistar大鼠高脂饲料喂养一个月后予链脲佐菌素（STZ）腹腔注射，复制糖尿病大鼠模型，将造模成功大鼠随机分成DM模型组，中药实验组，西药对照组，同时设立正常对照组。中药实验组予榛花消肾胶囊灌胃，西药对照组予罗格列酮合苯那普利做阳性对照。观察大鼠一般状态，检测血糖、血脂、肾功、尿量、尿微量白蛋白等变化。
2应用光学显微镜和透视电镜观察肾组织超微结构，观察榛花消肾胶囊对糖尿病大鼠肾脏病理组织结构的改变。
3采用免疫组化方法观察足细胞标志性分子nephrin、desmin、zo-1的蛋白表达；应用荧光定量PCR技术检测nephrin、desmin m RNA表达。
4采用免疫组化方法观察足细胞转分化wnt/β-catenin通路相关分子wnt-1、β-catenin、sail1蛋白表达；应用荧光定量PCR技术检测wnt-1、sail1m RNA表达。
结果：
1榛花消肾胶囊能够改善实验性DM大鼠的一般状态以及多饮、多食、多尿、消瘦的临床症状。
2榛花消肾胶囊对实验性DM大鼠具有一定的降血糖、降低甘油三酯和胆固醇的作用，改善糖脂代谢。
3榛花消肾胶囊能够抑制实验性DM大鼠早期肾脏肥大，减少尿微量白蛋白的排出，降低血肌酐和尿素氮，改善肾功能。
4榛花消肾胶囊具有改善实验性DM大鼠肾脏组织的病理形态，减轻肾小球基底膜增厚，细胞外基质的积聚，系膜增生，改善足细胞形态，从而减轻DM性肾小球硬化。
5榛花消肾胶囊具有抑制实验性DM大鼠肾组织nephrin、zo-1蛋白及m RNA的表达，增加desmin蛋白及m RNA的表达。
6榛花消肾胶囊具有抑制实验性DM大鼠肾组织转分化wnt/β-catenin通路中wnt-1、β-catenin、sail1蛋白及m RNA的表达。
结论：榛花消肾胶囊能够改善实验性DM大鼠一般状态以及多饮、多食、多尿、消瘦的症状；抑制早期肾脏肥大，减轻肾组织病理结构；具有降血糖、降低甘油三酯和胆固醇、减少尿微量白蛋白，降低血肌酐和尿素氮的作用。同时，榛花消肾胶囊亦能改善足细胞相关分子nephrin、zo-1、desmin表达，抑制足细胞转分化wnt/β-catenin信号转导通路分子wnt-1、β-catenin、sail1表达。说明榛花消肾胶囊是通过干预足细胞转分化wnt/β-catenin通路而发挥改善糖、脂代谢，减少尿蛋白，改善肾功的作用。
导师南征教授认为消渴肾病的病机关键是毒损肾络，邪伏膜原。创造性地将中医学毒损肾络、邪伏膜原理论与西医学糖尿病肾病发病机制，肾小球滤过膜-足细胞结构及功能联系在一起。榛花消肾胶囊在解毒通络、疏利膜原、益肾导邪的治疗大法指导下，通过干预足细胞转分化wnt/β-catenin通路而发挥治疗糖尿病肾病的作用。
Propose: Diabetic nephropathy (DN) is a common and serious diabetic complication ofblood vascular. The main features of DN are proteinuria and renal function changes.The mainpathological changes are glomerular filtration change, thickening of the basement membrane,mesangial cells widened, glomerular sclerosis, until the renal failure. Its high incidence andfast progress is a serious threat to human health.
The pathogenesis of diabetic nephropathy is more complex. In recent years, for the pointof view of the mechanism of proteinuria, podocyte has become a hot research. All factorsinjury podocyte will be involved in proteinuria, so the drug for improving podocyte functionbecomes hot spot and innovation in treatment of diabetic nephropathy. For the treatment ofdiabetic nephropathy proteinuria, Western medicine mainly adopt degraded blood glucosedrugs, ACEI/ARB drugs, improving circulatory drugs, until dialysis therapy whenintermediate stage or advanced stage. And traditional Chinese medicine in the treatment ofproteinuria has fine effective, which the western medicine can not be matched.ZhenHuaXiaoShen capsule my advisor commonly used is a prescription in the treatment ofdiabetic nephropathy proteinuria, which achieves satisfactory effect in clinical patients. Thisexperiment observes the influence of podocyte correlated molecules and podocyte EMT inwnt/β-catenin signal transduction pathway by ZhenHuaXiaoShen capsule interventionexperimental diabetic rats. And further evidence of ZhenHuaXiaoShen capsule for thetreatment of diabetic nephropathy proteinuria is effective.
Method:
1Wistar rats being feed with hypsi-lipoids feeder for a month has been intraperitonealinjected with streptozotocin (STZ) for making diabetic rat model. The successful DM rats arerandomly divided into DM model group, the experimental group with traditional Chinesemedicine, the control group with western medicine, and normal control group.ZhenHuaXiaoShen capsule has been used in the experimental group, while rosiglitazone andbenazepril has been used together in the control group. Observed rats the general state, testingthe blood glucose, blood lipids, renal function, urine output and urine micro albumin.
2Observed renal ultrastructure by optical microscope and perspective electronmicroscopy, and analyzed the renal organism pathological structure changes for ZhenHuaXiaoShen capsule intervention experimental diabetic rats.
3Observed the protein expression of podocyte signal molecule，like nephrin, desmin,zo-1by immunohistochemical method, and m RNA expression of nephrin, desmin byfluorescent quantitative PCR methods.
4Observed the protein expression of podocyte EMT related molecules, like wnt-1、β-catenin、snail1in wnt/β-catenin signal transduction pathway by immunohistochemicalmethod, and m RNA expression of wnt-1, snail1by fluorescent quantitative PCR.
Result:
1ZhenHuaXiaoShen capsules can improve the experimental DM rats the general stateand clinical symptoms, such as polydipsia, polyphagia, polyuria and athrepsy.
2ZhenHuaXiaoShen capsules can degrade the experimental DM rats blood glucose,triglyceride, cholesterol in a certain degree, and improve glycometabolism and lipidmetabolism.
3ZhenHuaXiaoShen capsule can inhibit the experimental DM rats the early renalhypertrophy, reduce urinary albumin discharge, degrade serum creatinine and blood ureanitrogen, improve renal function.
4ZhenHuaXiaoShen capsules improve the experimental DM rats nephridial tissuepathology, reduce the thickening of the glomerular basement membrane, extracellular matrixaccumulation, mesangial hyperplasy, improve podocyte morphous, thereby reducing DMglomerulosclerosis.
5ZhenHuaXiaoShen capsule can inhibit the experimental DM rats nephridial tissueprotein and m RNA expression of nephrin and zo-1, increase protein and m RNA expressionof desmin.
6ZhenHuaXiaoShen capsule can inhibit the experimental DM rats nephridial tissueprotein and m RNA expression of wnt-1, β-catenin and sail1in wnt/β-catenin signaltransduction pathway.
Conclusion：
ZhenHuaXiaoShen capsules can improve the experimental DM rats the general state andclinical symptoms of polydipsia, polyphagia, polyuria and athrepsy; inhibit the early renalhypertrophy and relieve the renal pathological structure; degrade blood glucose, triglyceride,cholesterol, reduce urinary albumin discharge, degrade serum creatinine and blood urea nitrogen. ZhenHuaXiaoShen capsules can also improve podocyte correlated proteinexpression of nephrin, zo-1and desmin, inhibit the expression of wnt-1, β-catenin and sail1in podocyte EMT in wnt/β-catenin signal transduction pathway. Therefore,ZhenHuaXiaoShen capsules can improve glycometabolism and lipid metabolism, reduceurine protein, and protect renal function by the way of intervention in podocyte EMT in wnt/β-catenin signal transduction pathway.
My advisor NanZheng professor considers that the pathogenesis key of diabeticnephropathy is poison damaged renal meridian and hidden in pleurodiaphragmatic spaces.Creatively associate two theory of the traditional Chinese medicine theory of poison damagedrenal meridian and hidden in pleurodiaphragmatic spaces and western medicine diabeticnephropathy pathogenesis, glomerular filtration membrane-structure and function ofpodocytes together. ZhenHuaXiaoShen capsule could treat diabetic nephropathy in the way ofdetoxification-deoppilation meridian and pleurodiaphragmatic spaces-tonifying kidney-eliminate pathogen by intervention podocyte EMT in wnt/β-catenin signal transductionpathway.
引文
[1]张真真．中西医结合糖尿病肾病高峰论坛在京召开[N]．中国中医药报海外版，2011，01，08（1）.
[2]王先令，陆菊明，潘长玉，等．糖尿病前期尿白蛋白排泄率和微量白蛋白尿患病率的比较[J]．中华内科杂志，2004，43（3）：170-173．
[3]吕仁和，赵进喜，王越.糖尿病肾病临床研究评述[J].北京中医药大学学报，1994，17(2):21.
[4]杨霓芝，王立新，廖平平.248例糖尿病肾病患者分期辨证分析.广州中医药大学学报，1998，15(4):260-262.
[5]成玉斌，罗仁，胡志飞，等.糖尿病肾病中医辨证分型荟萃分析[J].中国中医基础医学杂志，2000，6(5):49.
[6]熊玮．2型糖尿病肾病证候分布调查及早期主证治疗[J]．浙江中医杂志，2006，41(8):437-438．
[7]牟新，周旦阳，赵进喜.265例糖尿病肾病肾功能不全患者中医证候学研究[J].新中医，2007，39(5)：84-85.
[8]武曦蔼，倪青，李平.213例糖尿病肾病的中医证候分布调查.北京中医药，2009年1月第28卷第1期.
[9]王建萍.126例糖尿病肾病中医辨证分析[J].光明中医，2010，25(2):252-253.
[10]司富春，李建省.中医药治疗糖尿病肾病证型方药分析[J].中医研究，2010，23(8)：26-28.
[11]丁英钧，王世东，王颖辉，等.糖尿病肾病中医证候分布研究[J].北京中医药大学学报，2010，33(10)：695-696.
[12]李青，张惠敏，费宇彤.中西医结合治疗糖尿病肾病多中心前瞻性队列研究.中国中西医结合杂志，2012年3月第32卷第3期.
[13]专科专病名医临证丛书，糖尿病（第2版），人民卫生出版社，2006年.
[14]林莹宣，张静，曾静.亓鲁光治疗糖尿病肾病经验撷要.山西中医，2009年1月第25卷第1期，6-7.
[15]耿嘉，王丹，朴胜华等.栗德林教授辨治糖尿病肾病的学术思想简介.中国中西医结合肾病杂志，2005年5月第6卷第5期.
[16]刘松岩，于世家.于世家教授中西医结合治疗糖尿病肾病经验[J]中医药学刊.2006，24(12)：2189-2190.
[17]刘铜华.糖尿病肾病“络脉症瘕”说及其相关研究[C].北京中医药大学博士后研究工作报告，1999：14-15.
[18]赵迪.高彦彬教授治疗糖尿病肾病学术思想和经验[J].中医研究.2007.20(1)：42-44.
[19]仝小林，张志远，李宁.糖尿病肾病的中医治疗[J].中国医药学报，1998，13(4)：50-53.
[20]张彤，叶景华治疗继发性肾脏病经验撷英[J].中国中医药信息杂志,2007,12:81-82.
[21]宋恩峰，张珏，丁庆余.基于五行学说立法组方治疗糖尿病肾病的临床研究[J].湖北中医学院学报，2010，12(3)：50-52.
[22]唐咸玉.范冠杰教授治疗糖尿病的经验[J].中医药学刊，2006，24（2）：215-216.
[23]倪青，庞国明，孔宪遂.糖尿病肾病的中医药研究思路与方法[J].中国医药学报，1998，13(4)：60-62.
[24]张先闻，陈以平．陈以平辨治糖尿病肾病经验撷要[J]．上海中医药杂志，2008，42（6）：6-7．
[25]陶毅，张军，李晨．韩乐兵治疗糖尿病肾病的经验[J]．湖北中医杂志，2007，29（7）：24．
[26]薛国忠，戴恩来．刘宝厚教授治疗糖尿病肾病经验[J]．中国中西医结合肾病杂志，2007，8（6）：314-315．
[27]黄学民，赵进喜.糖尿病肾病的中医分期分型辨证探讨[J].中国老年保健医学，2005，3(1)：28.
[28]南劲松等.南征医学文集[M].长春：长春出版社，2008.
[29]王利民，李桂香．中西医结合治疗糖尿病肾病的临床观察[J]．中医药信息，2005，22(4):62-63．
[30]周清华．六味地黄汤加减治疗2型糖尿病早期肾病60例[J]．光明中医2011，26(1):71-72．
[31]陈志刚．瓜蒌瞿麦丸治疗糖尿病肾病蛋白尿的临床观察[J]．长春中医药大学学报，2009，25（1）：92．
[32]阎奇，刘鹰．血府逐瘀汤为主治疗糖尿病肾病48例疗效观察[J].中国中医药信息杂志，2007，14(4)：70-71.
[33]刘玉玲．参芪地黄汤加减治疗糖尿病肾病３０例[J]．陕西中医，2007，28(8)：981-982.
[34]刘小菊，叶玉珠.补阳还五汤加减治疗早期糖尿病肾病58例[J].浙江中西医结合杂志，2008，18(9):557.
[35]蓝柳贵，彭万年，朱章志，等.加味真武汤治疗糖尿病肾病少阴证60例临床观察[J].国医论坛，2006，21(2):7-8.
[36]张秋林，罗宏斌，冉燕雪，等.金锁固精丸加味方联合福辛普利治疗糖尿病肾病临床观察[J].新中医,2009,41(1):23-24.
[37]谌洁，苏经格，益气养阴活血方治疗糖尿病肾病30例临床研究[J].中医杂志，2006，47(11):841-843.
[38]李乐梅.猪苓汤合膈下逐瘀汤治疗糖尿病肾病30例临床研究[J].中医杂志，2002，43(3):189-190.
[39]周玉来.当归六黄汤治疗早期糖尿病肾病33例[J].中医研究，2008，21(5)：37-38.
[40]李世云，牛素蒲，韩松林.利百苓治疗早期糖尿病肾病水肿21例临床观察[J].实用中医内科杂志，2008，22(3)：41.
[41]庞晓英，高继宁，钱雅玉．玉液汤治疗糖尿病肾病所致慢性肾功能不全临床观察[J]．上海中医药杂志，2006，40(9):43-44．
[42]钟彧，钟奡，中西医结合治疗糖尿病肾病临床疗效分析，中国实用医药，2009年5月第4卷第13期：52-53.
[43]王廷春.加味桃核承气汤治疗糖尿病肾病138例临床观察[J].国医论坛，2000，15(2):10.
[44]毛阵营.五苓散合血府逐瘀汤治疗糖尿病肾病160例[J].光明中医，2003，18(6)：9-10.
[45]胡卫芬.益糖宁颗粒剂治疗糖尿病肾病血瘀证60例临床观察[J].中国中医药科技，2006，11(1)：53-54.
[46]敖绍勇，吴正平.中西医结合治疗早期糖尿病肾病临床观察[J].宜春医学院学报，2006，28(2):125-126.
[47]胡孝荣，朱小刚，陈颖．济生肾气丸治疗临床期糖尿病肾病的临床研究．四川中医，2005，23(7):38-39．
[48]郑勇，黄达勤.玉泉丸对早期糖尿病肾病肾损害指标的影响.现代中药研究与实践2005，19(2):42-44.
[49]周旭生.加减藿朴夏苓汤治疗糖尿病肾病32例[J].吉林中医药，2003，23(2):16.
[50]高书荣.左归丸治疗2型糖尿病肾病临床观察.中成药，2004，26(1):10.
[51]刘翠豹，张冀宁，赵建新．升降汤对临床期糖尿病肾病的疗效观察．中国中医基础医学杂志，2011，17(7):811．
[52]李帆.大黄虫丸对糖尿病肾病蛋白尿的疗效观察[J].海南医学，2007，18(6)：85-86.
[53]牛志勇.从“瘀”立论治疗糖尿病肾病92例临床分析.光明中医.2012年7月第27卷第7期，1330-1331.
[54]王凡，姜梅玲，朱虹.清热化痰方治疗早中期糖尿病肾病30例.中国中医药现代远程教育，2012年第10卷第14期总第142期，14-15.
[55]王刚胡，金焕，边东.糖肾保元方联合雷公藤多苷片对糖尿病肾病Ⅳ期患者24小时尿蛋白定量的影响，实用医学杂志2012年第28卷第11期.
[56]王惠玲，司海龙.糖肾康方治疗早期糖尿病肾病30例临床观察,山西中医2012年9月第28卷第9期，14-15.
[57]熊晓东，张玉琴.温阳降浊法中药治疗糖尿病肾病临床观察，辽宁中医药大学学报第14卷第8期2012年8月，196-198.
[58]补肾活血方联合曼新妥、佰塞通参芎葡萄注射液治疗糖尿病肾病慢性肾功能衰竭的临床观察，王立范，李莲花，李淑菊，中医药学报，2011年第39卷第3期，58-59.
[59]盖云，张彤，杨晓萍.叶氏益气软坚方结合西医常规疗法治疗糖尿病肾病Ⅳ期疗效观察，第二军医大学学报，2011年7月第32卷第7期.
[60]杨李，杨教会，田青.自拟芪莲汤治疗早期糖尿病肾病43例，中国药师2011年第14卷第6期841-842.
[61]王建生.补肾化瘀利水法治疗糖尿病肾病临床观察，蚌埠医学院学报，2010年1月第35卷第1期67-69.
[62]唐晨光，潘勤，陈腾云.消渴漏微方治疗早期糖尿病肾病的临床研究，新中医2010年2月第42卷第2期.
[63]白桦，刘法，杨建萍.九味地黄汤治疗中老年早期糖尿病肾病临床观察，内蒙古中医药，2009年第2期1-4.
[64]马建伟，徐丽梅，马新英.滋肾通络祛浊法治疗糖尿病肾病肾功能不全失代偿期临床研究，安徽中医学院学报，2009年12月第28卷第6期28-30.
[65]孔凡俊，中西医结合治疗早期糖尿病肾病50例临床观察，实用中西医结合临床2011年3月第11卷第2期.
[66]刘春倩，孟爱霞，黄吉峰，等．李显筑教授治疗糖尿病肾病经验[J]．长春中医药大学学报，2009，25（1）：10-11．
[67]韩吉祥，代清湘，常琼等，中西医联合治疗早期糖尿病肾病疗效观察，四川中医，2010年第28卷第4期.
[68]田素娟等．黄芪联合低分子肝素钙治疗老年性糖尿病肾病Ⅲ-Ⅳ期蛋白尿的疗效观察[J]．中华当代医学，2007，5(4):30．
[69]蒋忠华．葛根素注射液治疗50例早期糖尿病肾病疗效观察[J]．浙江临床医学，2007，7（9）：925．
[70]胥勋梅，夏芳，马勋龙，等．红花注射液治疗糖尿病肾病的疗效观察[J]．现代医药卫生，2007，23（7）：993-994．
[71]史伟，吴金玉，向彩春，等.水蛭注射液治疗糖尿病肾病57例[J].陕西中医，2007，28(4):401-403.
[72]杨彦，熊萍．川芎嗪注射液对23例糖尿病肾病患者血糖、尿蛋白及Ｃ反应蛋白的影响[J]．江苏中医药，2008，40（1）：34-35．
[73]魏玉菊，唐梅森.丹红注射液治疗糖尿病肾病的疗效观察[J].光明中医，2009，24(11):2112-2114.
[74]陈军宁，李作兴，韦广粤，等．银杏达莫注射液对早期糖尿病肾病炎性细胞因子的影响[J]．吉林医学，2010，31(22):3709-3710．
[75]郝玉杰，王运红，王桂英，等．肾康注射液对早期糖尿病肾病尿内皮素及血脂血黏度的影响[J]．河北医科大学学报，2010，31(2):136-138．
[76]田沛文，王静军，王雪琴.中西医结合治疗早期糖尿病肾病临床观察[J].山西中医，2008，24(8):24.
[77]朗江明，曹海伟，魏爱生，等.血栓通与血栓通与抵克立得治疗早期糖尿病肾的对比研究[J].中国中西医结合杂志，1998，18（12）：727-729.
[78]王文雄.苦碟子注射液治疗糖尿病肾病58例[J].药物与临床，2007，4（4）：135-136.
[79]姚春.丹参酮ⅡA注射液治疗早期糖尿病肾病的临床观察[J].现代医药卫生，2008，24(2):251.
[80]黄各宁，陈积优，张镁元.灯盏花素注射液对糖尿病肾病血液流变学影响的临床研究[J].新中医，2006，38(3):34-35.
[81]陆芝兰.刺五加注射液治疗早期糖尿病肾病64例临床观察[J].中医药导报，2007，13(7):40-41.
[82]赵宁，王鸣，费晓，等.参附注射液对早期DN血液D-D二聚体，Fib，CRP的影响[J].浙江中西医结合杂志，2007，17(8):476-478.
[83] Dalla vestra M, Masiero A, Roiter AM, et al. Is podocyte injury relevantin diabeticnephropathy studies in patients with type2diabetes [J].Diabetes,2003,52(4).
[84] Mundel P，ShanklandS J.Podocyte biology and response to injury[J].JAmSoc Nephrol，2002；13(12):3005-3015.
[85] LemleyKV，Abdullah I，Myers BD，Meyer TW，Blouch K，Smith WE，Bennet PH，Nelson RG.Evolution of incipient nephropathy in type2diabetes mellitus[J]. KidneyInt，2000，58:1228-1237.
[86] Pavenstadt H. Roles of the podocyte in glomerular function.[J] Am J Physiol RenalPhysiol.2000,278(2): F173-F179.
[87] Floege J，Alpers CE，Saqe EH，et al.Markers of complement-dependent andcomplement-independent glomerular visceral epithelial cell injury in vivo.Expression ofantiadhesive proteins and cytoskeletal ehanges.Lab Invest，1992:67(4):486-497.
[88] Wartio vaara J, Ofvrstedt LG, Khoshnoodi J, et al. Nephrin strands contribute to aporous slit diaphragm scaffold as revealed by electrontomography [J]. J Clin Invest,2004,114(7):1475-1483.
[89] Cooper ME, Mundel P, Boner G. Role of nephrin in renal disease including diabeticnephropathy.[J]. Semin Nephrol,2002,22(5):398.
[90] Caridi G, Perfumo F, Ghiggeri GM. NPHS2(Podocin) mutations in nephrotic syndrome.Clinical spectrum and fine mechanisms [J] Pediatr Res,2005,57(5Pt2):54R-61R.
[91] Huber TB, Schmidts M, Gerke P, etal. The carboxy termi-nus of Neph family membersbinds to the PDZ domain protein zonula occludens-1.[J] J Biol Chem,2003,278(15):13417-13421.
[92] Inoue T, Yaoita E, Kurihara H, etal. FAT is a comment ofglomeru-lar slit diaphragms.[J]Kidney Int,2001,59(3):1003-1012.
[93] Raats CJ, van den Born J, Bakker MA, et al. Expression of agrin, dystroglycan andutrophin in normal renal tissue and in experimental glomerulo pathies.Am JPathol,2000,156(5):1749-1765.
[94] Barisoni L，KoPP JB.Update in podocyte biology:putting one's，best foot forward. CurrOpin Nephrol Hypertens，2003;12(3):251-258.
[95] Takeda T，McQuistan T，Orlando RA，et al.Loss of glomerular foot processes isassociated with uncoupling of podocalyxin from the actin cytoskeleton.J Clin Invesr，2001，108:289-301.
[96] Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focalglomerulosclerosis.J Clin Invest，2001，108:1583-7.
[97] Kriz W, Gretz N，Lemley KV.Progression of glomerular diseases:is the podocyte theculprit [J].Kidney Int，1998，54(3):687-97.
[98] Xu ZG, Yoo TH, Ryu DR, et al. AngiotensinⅡreceptor blocker inhibits p27Kiplexpression in glucose-stimulated podocytes and in diabetic glomeruli. Kidney Int,2005,67(3):944-952.
[99] Petermann A, Hiromura K, Blonski M, et al. Mechanical stress reduces podocyteproliferation in vitro. Kidney Int,2002,61(1):40-50.
[100] Steffes MW, Schmidt D, Mccrery R, et al. Glomerular cell number in normal subjectsand in type1diabetic patients.[J] Kidney Int,2001,59(6):2104-2113.
[101]刘志红,李世军,陈朝红. DN患者足细胞病变的临床病理特征.[J]肾脏病透析与肾移植杂志,2003,12(2):144.
[102] Benigni A, Gagliardini E, Tomasoni S, et al. Selective mi-pairmentofgene expressionand assembly of nephrin in human diabetic nephropathy [J] Kidney Int,2004,65(6):2193-2200.
[103] Doublier S, Salvidio G, Lupia E, et al. Nephrin expression is reduced inhuman diabeticnephropathy: evidence for a distinct role for glycated albumin and angiotensinⅡ.[J]Diabetes,2003,52(4):1023-1030.
[104] Forbes JM, Bonnet F, Russo LM, t al. Modulation of nephrin in the diabetic kidney:association with systemic hypertension and increasing albuminuria. J Hypertens,2002,20(5):985-992.
[105] Toyoda M, Suzuki D, Umezono T, et al. Expression of human Nephrin mRNA indiabetic nephropathy.[J]. Nephrol Dial Transplant,2004,19(2):380-385.
[106] Chen HC, Chen CA, Guh JY, et al. Altering expression of alpha3beta1integrin onpodocytes of human and rats with Diabetes [J] Life Sci,2000,67(3):2345-2353.
[107] Blanco S, Vaquero M, Gomez-Guerrero C, et al. Potential role ofangiotensin-converting enzyme inhibitors and statins on early podocyte damage ina model of type2diabetes mellitus, obesity, andmild hypertension.[J] Am J Hypertens,2005,18(4):557-565.
[108]覃乔静，邓华聪，曹文富，等.血管紧张素II与糖尿病大鼠足细胞损害的实验研究[J].重庆医科大学学报，2004，29(4):448-451.
[109]吕智美,甘华.足细胞损伤与糖尿病[J].中华老年医学杂志,2005,24(1):67-71.
[110] Rincon-Choles H, Vasylyeva TL, Pergola PE, et al. ZO-1expression andphosphorylation in diabetic nephropathy [J].Diabetes,2006,55(4):894-900.
[111] Rincon-Choles H, Vasylyeva TL, Bhandari K, et al. Regulation of ZO-1expression andphosphorylation in experimental dia-betes. J Am Soc Nephrol,2003,14:47A.
[112] Cortes P,Mendez M，Riser BL，et al.F2actin fiber distribution in glomerular cells:structural and functional implications.Kidney Int，2000，58:2452.
[113] Siu B, Saha J, Smoyer WE, et al. Reduction in podocyte density as a pathologic featurein early diabetic nephropathy in rodents: prevention by lipoic acid treatment [J].BMCNephrol,2006,7:6.
[114] Dessapt C, Hargreaves R, Dei CA, et al. Modulation of alpha3-beta1integrinexpression and cell adhesion in glomerular podocytes by glucose and mechanicalstretch[J].Diabetic Med,2004,21(2):10-11.
[115] Koop K, Eikmans M, Baelde HJ, et al. Expression of podocyte associated molecules inacquired human kidney diseases. J Am Soc Nephrol,2003,14(8):2063-2071.
[116] Economou CG, Kitsiou PV, Tzina AK, et al. Enhanced podoca-lyxin expresing altersthe structure of podocyte basal surface. J Cell Sei,2004,117(Pt15):3281-3294.
[117] Nelson RG，Mmyer TW，Myers BD，et al.Clinical and pathological course of renaldisease innoninsulin-dependent diabetes mellitus: The Pima Indian experience，SeminNephrol，1997;17(2):124-131.
[118] Pagtaluma ME，Miller PL，Damping-Eagle S，et al.Podocyte Loss and ProgressiveGlomerular Injury in Type II Diabetes.J Clin Invest，1997;99(2):342-348.
[119] Kuusniemi AM，Merenmies J，Lahdenkari AT，et al. Glomerular sclerosis in kidneyswith congenital nephritic syndrome(NPHS1).Kidney Int，2006;70(8):1423-1431.
[120] Bariety J, Bruneval P, Meyrier A, et al. Podocyte involve-ment in human immunecrescentic glomerulonephritis [J]. Kidney Int,2005,68(3):109.
[121]吕智美，甘华.足细胞损伤与糖尿病[J].中华老年医学杂志.2005，24(l):67-71.
[122] Lee EY, Chung CH, Kim JH, et al. Antioxidants ameliorate the expression of vascularendothelial factor mediated by pro-tein kinase C in diabetic podocytes [J] Nephrol DialTrans-plant,2006,21(6):1496-1503.
[123] Benigni A, Tomasoni S, Gagliardini E, et al. Blocking angiotensin II synthesis/activitypreserves glomerular nephrin in rats with severe nephrosis [J] J Am SocNephrol,2001,12(3):941-948.
[124] Saleem MA, Ni L, Witherden I, et al. Co-localization of nephrin, podocin, and theactin cytoskeleton: evidence for a role in podocyte foot process formation. Am JPathol,2002,161(4):1459-1466.
[125] Toyoda M, Najafian B, Kmi Y, et al. Podocyte detachment and reduced glomerularcapillary endothelial fenestration in human type1diabetic nephropathy [J] Diabetes,2007,56(8):2155-2160.
[126] Okada T，Wada J，Hida K，et al. Thiazolidinediones arneliorate diabeticnephropathy via cell cycle-dependent mechanisms[J].Diabetes，2006，55(6):1666-1677.
[127] Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabeticnephropathy [J] Nephron Physiol,2007,106(2):26-31.
[128] Dessapt C, Hargreaves R, Dei CA, et al. Modulation of alpha3-beta1integrinexpression and cell adhesion in glomerular podocytes by glucose and mechanicalstretch[J].Diabetic Med,2004,21(2):10-11.
[129] Susztak K, Raff AC, Schiffer M, et al. Glucose-induced re-active oxygen species causeapoptosis of podocytes and podo-cyte depletion at the onset of diabetic nephropathy [J]Diabetes,2006,55(1):225-233.
[130] Kaplan JM, Kmi SH, North KN, et al. Mutations in ACTN4, encoding alpha-actinin-4,cause familial focal seg-mental glomerulosclerosis [J] NatGenet,2000,24(3):251-256.
[131] Baelde HJ, Eikmans M, Doran PP, et al. Gene expression profiling in glomeruli fromhuman kidneyswith diabetic ne-phropathy [J].Am J Kidney Dis,2004,43(4):
[132] Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glo-merulosclerosisand miplicates podocyte activation in the pathogenesis of diabetic nephropathy[J].Am JPathol，2003,162(4):1123-1137.
[133] Yoo TH, Li JJ, Kmi JJ, et al. Activation of the renin-angio-tensin system withinpodocytes in diabetes [J] Kidney Int,2007,71(10):1019-1027.
[134] Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabeticnephropathy [J] Nephron Physiol,2007,106(2):26-31.
[135] Iglesias-dela Cruz MC, Ziyadeh FN, Isono M, et al. Effects of high glucose and TGF-β1on the exp ression of collagen IV and vascular endothelial growth factor in mousepodocytes [J]. Kidney Int,2002,62(3):901-913.
[136] Cooper ME, Vranes D, Youssef S, et al. Increased renal expression of vascularendothelial growth factor (VEGF) and its receptor VEG-FR-2in experimental diabetes[J].Diabetes,1999,48(11):2229-2239.
[137] Chen S, Kasama Y, Lee JS,et al·Podocyte derived vascular endothelial growthfactormediates the stimulation of2α3(Ⅳ) collagen production by transforming growthfactor β1in mouse podocytes [J]·Diabetes,2004,53(11):2939-2949.
[138] Cummings E A, Sochett EB, Dekker MG, et al. Contribution of growth hormone andIGF-1to early diabetic nephropathy in type1diabetes. Diabetes,1998,47(8).
[139] Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovasculardisease in patients with type2diabetes[J].N Engl J Med,2003,348(5):383-393.
[140] Trelstad RL，Revel JP，Hay ED. Tight junctions between cells in the early chickelmbryo as visualized with the electron microscopy. The Joumal of cellbiology.1966Oct;31(1):C6-10.
[141] Hay RJ，Menzies RA，Morgan HP，Strehler BL.The division potential of cells incontinuous growth as compared to cells subcultivated after maintenance in stationaryphase.Experimental gerontology.1968Mar;3(1):35-44.
[142] Berardi R，Scartozzi M，Romagnoli E，Antognoli S，Cascinu S:Gastric cancertreatment: A systematic review.Oncol Rep2004;11:911-916.
[143] Pisani P，Bray F，Parkin DM:Estimates of the world-wide prevalence of cancer for25sites in the adult population.Int J Cancer2002:97:72-81.
[144] Ng YY，Huang TP，Yang WC，Chen ZP，Yang AH，Mu W，Nikolie-Paterson DJ，Atkins RC，Lan HY:Tubular epithelial-myofibroblast transdifferentiation in progressivetubulointerstitial fibrosis in5/6nephrectomized rats.Kidney Int1998;54:864-876.
[145] Ohkubo T，Ozawa M.The transcription factor Snail downregulates the tight junctioncomponents independently of E-cadherin downregulation[J].Cell Sci，2004，117(Ptg):1675-1685
[146] Jethwa P，Naquvi M，Hardy RG,et al.Overexpression of Slug is associated withmalignant progression of esophageal adenocarcinoma[J].World J Gastroentrol，2008，14(7):1044-1052.
[147] Reidy K, Susztak K. Epithelial-mesenchymal transition and podocyte loss in diabetickidney disease.Am J Kidney Dis,2009,54(4):590-593.
[148] Yam aguchi Y, Iwano M, Suzuki D, et al. Epithelial-mesenchymal transition as anexplanation for podocyte depletion in diabetic nephropathy.Am J Kidney D is,2009,54(4):653-664.
[149] Daisuke S,Yohei M,Tatsuyo N,et al.Amelioration of renal alterations in obese type2diabetic mice by vasohibin-1,a negative feedback regulator of angiogenesis.AJP-RenalPhysiol,2011,4:873-886.
[150] Li Y, Kang YS, Dai C,et al. Epithelial-to-mesenchymal transition is a potential pathwayleading to podocyte dysfunction and poteinuria[J].Am J Pathol,2008,172(2):299-308.
[151] Kang YS,Li Y,Dai C, et al.Inhibition of integrin-linked kinase blocks podocyteepithelial-mesenchymal transition and am eliorates proteinuri-a.Kidney Int,2010,78(4):363-373.
[152] Veeman MT,Axelrod JD,Moon RT.A second canon:functions and mechanisms ofbeta-catenin-independent Wnt signaling.Dev Cell,2003,5:367-377.
[153] Mariappan MM, Shetty M, Sataranatarajan K,et al.Glycogen synthase kinase3beta is anovel regulator of high glucose-and high insulin-induced extracellular matrix proteinsynthesis in renal proximal tubular epithelial cells.J Biol Chem,2008,283(45).
[154] Medici D,Hay ED,Olsen BR.Snail and Slug promote epithelial-mesenchymal transitionthrough beta-catenin-T-cell factor-4-dependent expression of transforming growthfactor-beta3.Mol BiolCell,2008,19(11):4875-87.
[155] Kim K, Lu Z,Hay ED.Direct evidence for a role of beta-catenin/LEF-1signalingpathway in induction of EMT.Cell Biol Int,2002,26(5):463-76.
[156] Jong In Yook,Xiao-Yan Li,Ichiro Ota,et al.Wnt-dependent regulation of the E-cadherinrepressor snail.J BiolChem,2005,280(12):11740-48.
[157] Coward RJ, Welsh GI, Yang J, et al. The human glomerular podocyte is a novel targetfor insulin action [J] Diebetes,2005,54(11):3095-3102.
[158] Nakamura T, Ushiyama C, Osada S, et al. Pioglitazone reduces urinary podocyteexcretion in type2diabetes patients with microal buminuria. Metabolish,2001,50(10):1193-1196.
[159] Kuhlmann A，Haas CS，Gross ML，et al.1,25-Dihydroxyvitamin D3decreases podocyteloss and podocyte hypertrophy in the subtotally nephrectomized rat [J].Am J physiolRenal Physiol，2004，286(3):F526-33.
[160] Wolf G, Chen S，Ziyadeh FN. From the periphery of the glomerular capillary walltoward the center of disease: podocyte injury comes of age in diabetic nephropathy,Diabetes，2005，54(6):1626-1634.
[161] Mifsud SA，Allen TJ，Bertram JF，et al.Podocyte foot process broadening inexperimental diabetic nephropathy:amelioration with renin-angiotensin blockade.Diabetologia，2001，44:878-82.
[162] Gross ML，EI-Shakmak A，Szabo A，et al.ACE-inhibitors but not endothelin receptorblockers prevent podocyte loss in early diabetic nephropathy.Diabetologia，2003，46.
[163] Gross ML，Ritz E，Schoof A，et al. Renal damage in the SHRI/N-cp type2diabetesmodel:comparison of an angiotensin-converting enzyme inhibitor and endothelinreceptor blocker[J].Lab Invest，2003，83(9):1267-77.
[164] Davis BJ, Cao Z, de Gaparo M, et al. Disparate effects of angiotensin Ⅱantagonistsand calcium channel blockers on albuminuria in experimental diabetes andhypertension: potential role of nephrin.[J].J Hypertens,2003,21(1):209-16.
[165]魏洪坤，方敬爱，孙艳艳，等.肾炎康复片对糖尿病肾病大鼠肾组织podocalyxin表达的影响[J].中国中西医结合肾病杂志，2009,10（6）：485-488.
[166]陈姝君，陈海平，刘奇.尿毒清颗粒对糖尿病大鼠足细胞损伤的保护作用研究[J].中国中西医结合肾病杂志，2008,9（10）：875-878.
[167] Zhang P, Zhang J J, Su J, et al. Effect of total glucosides of paeony on the expression ofnephrin in the kidneys from diabetic rats[J]. Am J ChinMed,2009,37(2):295.
[168]许洪燕，方敬爱，张晓东，等.益肾胶囊对糖尿病肾病模型肾小球足细胞的影响[J].中国中西医结合肾病杂志,2009，10(7):577.
[169] Wolf G，Chen S，Ziyadeh FN. From the periphery of the glomerular capillary walltoward the center of disease：pocyte injury comes of age in diabeticnephropathy[J].Diabetes，2005，54：1626-1634.
[170]仝小林.糖尿病中医防治指南解读[M].北京：中国中医药出版社，2009:55.
[171]陈灏珠．实用内科学:七册［M］．12版．北京:人民卫生出版社，2005:1015.
[172]任继学，任继学经验集．北京：人民卫生出版社，2009.
[173] Durvasu la RV，Shank land SJ. Podocyte injury and targeting therapy an update CurrOpin Nehprol Hypertena，2006，15(1):1-7.
[174] Lin CL，Wang JY，Huang YT，et al. Wnt/beta-catenin signaling modulates survival ofhigh glucose-stressed mesangial cells.J Am Soc Nephrol，2006，17:2812-20.
[175] Dai C.，Stolz D.B.，Kiss L.P.，et al. Wnt/beta-catenin signaling promotes podocytedysfunction and albuminuria.J.Am.Soc.Nephrol.,2009,20:1997-2008.
[176] ZHA Yun Hong，MEI YuanWu，MAO Ling.The Advantages for Snail Expression toPromote Cell Migration and Induce Actin Reorganization and to Protect Against theSerum deprivation triggered Apoptosis of Bone Marrow Stem Cells.Journal ofBiotechnology.2007,23(4)645-651.
[177] Miyoshi A，Kitajima Y，Sumi K，et al.Snail and SIPI increase cancer invasion byupregulation MMP family in hepatocellular carcinoma cell.Br JCancer.2004,90:1265-1273.
[178] Yokoyama K，Kamata N，Fujimoto R，et al.Increased invasion and matrixmetalloproteinase-2expression by Snail-induced mesenchymal transition in squamouscell carcinomas.Int J Oncol.2003,22(4):891.
[179] Brunner F P，Thiel G，Hermle M，et al.Long-term enalapril and verapamil in rats withreduced renal mass.Kidney Int.1989.36(6):969-977.
[2]王先令，陆菊明，潘长玉，等．糖尿病前期尿白蛋白排泄率和微量白蛋白尿患病率的比较[J]．中华内科杂志，2004，43（3）：170-173．
[3]吕仁和，赵进喜，王越.糖尿病肾病临床研究评述[J].北京中医药大学学报，1994，17(2):21.
[4]杨霓芝，王立新，廖平平.248例糖尿病肾病患者分期辨证分析.广州中医药大学学报，1998，15(4):260-262.
[5]成玉斌，罗仁，胡志飞，等.糖尿病肾病中医辨证分型荟萃分析[J].中国中医基础医学杂志，2000，6(5):49.
[6]熊玮．2型糖尿病肾病证候分布调查及早期主证治疗[J]．浙江中医杂志，2006，41(8):437-438．
[7]牟新，周旦阳，赵进喜.265例糖尿病肾病肾功能不全患者中医证候学研究[J].新中医，2007，39(5)：84-85.
[8]武曦蔼，倪青，李平.213例糖尿病肾病的中医证候分布调查.北京中医药，2009年1月第28卷第1期.
[9]王建萍.126例糖尿病肾病中医辨证分析[J].光明中医，2010，25(2):252-253.
[10]司富春，李建省.中医药治疗糖尿病肾病证型方药分析[J].中医研究，2010，23(8)：26-28.
[11]丁英钧，王世东，王颖辉，等.糖尿病肾病中医证候分布研究[J].北京中医药大学学报，2010，33(10)：695-696.
[12]李青，张惠敏，费宇彤.中西医结合治疗糖尿病肾病多中心前瞻性队列研究.中国中西医结合杂志，2012年3月第32卷第3期.
[13]专科专病名医临证丛书，糖尿病（第2版），人民卫生出版社，2006年.
[14]林莹宣，张静，曾静.亓鲁光治疗糖尿病肾病经验撷要.山西中医，2009年1月第25卷第1期，6-7.
[15]耿嘉，王丹，朴胜华等.栗德林教授辨治糖尿病肾病的学术思想简介.中国中西医结合肾病杂志，2005年5月第6卷第5期.
[16]刘松岩，于世家.于世家教授中西医结合治疗糖尿病肾病经验[J]中医药学刊.2006，24(12)：2189-2190.
[17]刘铜华.糖尿病肾病“络脉症瘕”说及其相关研究[C].北京中医药大学博士后研究工作报告，1999：14-15.
[18]赵迪.高彦彬教授治疗糖尿病肾病学术思想和经验[J].中医研究.2007.20(1)：42-44.
[19]仝小林，张志远，李宁.糖尿病肾病的中医治疗[J].中国医药学报，1998，13(4)：50-53.
[20]张彤，叶景华治疗继发性肾脏病经验撷英[J].中国中医药信息杂志,2007,12:81-82.
[21]宋恩峰，张珏，丁庆余.基于五行学说立法组方治疗糖尿病肾病的临床研究[J].湖北中医学院学报，2010，12(3)：50-52.
[22]唐咸玉.范冠杰教授治疗糖尿病的经验[J].中医药学刊，2006，24（2）：215-216.
[23]倪青，庞国明，孔宪遂.糖尿病肾病的中医药研究思路与方法[J].中国医药学报，1998，13(4)：60-62.
[24]张先闻，陈以平．陈以平辨治糖尿病肾病经验撷要[J]．上海中医药杂志，2008，42（6）：6-7．
[25]陶毅，张军，李晨．韩乐兵治疗糖尿病肾病的经验[J]．湖北中医杂志，2007，29（7）：24．
[26]薛国忠，戴恩来．刘宝厚教授治疗糖尿病肾病经验[J]．中国中西医结合肾病杂志，2007，8（6）：314-315．
[27]黄学民，赵进喜.糖尿病肾病的中医分期分型辨证探讨[J].中国老年保健医学，2005，3(1)：28.
[28]南劲松等.南征医学文集[M].长春：长春出版社，2008.
[29]王利民，李桂香．中西医结合治疗糖尿病肾病的临床观察[J]．中医药信息，2005，22(4):62-63．
[30]周清华．六味地黄汤加减治疗2型糖尿病早期肾病60例[J]．光明中医2011，26(1):71-72．
[31]陈志刚．瓜蒌瞿麦丸治疗糖尿病肾病蛋白尿的临床观察[J]．长春中医药大学学报，2009，25（1）：92．
[32]阎奇，刘鹰．血府逐瘀汤为主治疗糖尿病肾病48例疗效观察[J].中国中医药信息杂志，2007，14(4)：70-71.
[33]刘玉玲．参芪地黄汤加减治疗糖尿病肾病３０例[J]．陕西中医，2007，28(8)：981-982.
[34]刘小菊，叶玉珠.补阳还五汤加减治疗早期糖尿病肾病58例[J].浙江中西医结合杂志，2008，18(9):557.
[35]蓝柳贵，彭万年，朱章志，等.加味真武汤治疗糖尿病肾病少阴证60例临床观察[J].国医论坛，2006，21(2):7-8.
[36]张秋林，罗宏斌，冉燕雪，等.金锁固精丸加味方联合福辛普利治疗糖尿病肾病临床观察[J].新中医,2009,41(1):23-24.
[37]谌洁，苏经格，益气养阴活血方治疗糖尿病肾病30例临床研究[J].中医杂志，2006，47(11):841-843.
[38]李乐梅.猪苓汤合膈下逐瘀汤治疗糖尿病肾病30例临床研究[J].中医杂志，2002，43(3):189-190.
[39]周玉来.当归六黄汤治疗早期糖尿病肾病33例[J].中医研究，2008，21(5)：37-38.
[40]李世云，牛素蒲，韩松林.利百苓治疗早期糖尿病肾病水肿21例临床观察[J].实用中医内科杂志，2008，22(3)：41.
[41]庞晓英，高继宁，钱雅玉．玉液汤治疗糖尿病肾病所致慢性肾功能不全临床观察[J]．上海中医药杂志，2006，40(9):43-44．
[42]钟彧，钟奡，中西医结合治疗糖尿病肾病临床疗效分析，中国实用医药，2009年5月第4卷第13期：52-53.
[43]王廷春.加味桃核承气汤治疗糖尿病肾病138例临床观察[J].国医论坛，2000，15(2):10.
[44]毛阵营.五苓散合血府逐瘀汤治疗糖尿病肾病160例[J].光明中医，2003，18(6)：9-10.
[45]胡卫芬.益糖宁颗粒剂治疗糖尿病肾病血瘀证60例临床观察[J].中国中医药科技，2006，11(1)：53-54.
[46]敖绍勇，吴正平.中西医结合治疗早期糖尿病肾病临床观察[J].宜春医学院学报，2006，28(2):125-126.
[47]胡孝荣，朱小刚，陈颖．济生肾气丸治疗临床期糖尿病肾病的临床研究．四川中医，2005，23(7):38-39．
[48]郑勇，黄达勤.玉泉丸对早期糖尿病肾病肾损害指标的影响.现代中药研究与实践2005，19(2):42-44.
[49]周旭生.加减藿朴夏苓汤治疗糖尿病肾病32例[J].吉林中医药，2003，23(2):16.
[50]高书荣.左归丸治疗2型糖尿病肾病临床观察.中成药，2004，26(1):10.
[51]刘翠豹，张冀宁，赵建新．升降汤对临床期糖尿病肾病的疗效观察．中国中医基础医学杂志，2011，17(7):811．
[52]李帆.大黄虫丸对糖尿病肾病蛋白尿的疗效观察[J].海南医学，2007，18(6)：85-86.
[53]牛志勇.从“瘀”立论治疗糖尿病肾病92例临床分析.光明中医.2012年7月第27卷第7期，1330-1331.
[54]王凡，姜梅玲，朱虹.清热化痰方治疗早中期糖尿病肾病30例.中国中医药现代远程教育，2012年第10卷第14期总第142期，14-15.
[55]王刚胡，金焕，边东.糖肾保元方联合雷公藤多苷片对糖尿病肾病Ⅳ期患者24小时尿蛋白定量的影响，实用医学杂志2012年第28卷第11期.
[56]王惠玲，司海龙.糖肾康方治疗早期糖尿病肾病30例临床观察,山西中医2012年9月第28卷第9期，14-15.
[57]熊晓东，张玉琴.温阳降浊法中药治疗糖尿病肾病临床观察，辽宁中医药大学学报第14卷第8期2012年8月，196-198.
[58]补肾活血方联合曼新妥、佰塞通参芎葡萄注射液治疗糖尿病肾病慢性肾功能衰竭的临床观察，王立范，李莲花，李淑菊，中医药学报，2011年第39卷第3期，58-59.
[59]盖云，张彤，杨晓萍.叶氏益气软坚方结合西医常规疗法治疗糖尿病肾病Ⅳ期疗效观察，第二军医大学学报，2011年7月第32卷第7期.
[60]杨李，杨教会，田青.自拟芪莲汤治疗早期糖尿病肾病43例，中国药师2011年第14卷第6期841-842.
[61]王建生.补肾化瘀利水法治疗糖尿病肾病临床观察，蚌埠医学院学报，2010年1月第35卷第1期67-69.
[62]唐晨光，潘勤，陈腾云.消渴漏微方治疗早期糖尿病肾病的临床研究，新中医2010年2月第42卷第2期.
[63]白桦，刘法，杨建萍.九味地黄汤治疗中老年早期糖尿病肾病临床观察，内蒙古中医药，2009年第2期1-4.
[64]马建伟，徐丽梅，马新英.滋肾通络祛浊法治疗糖尿病肾病肾功能不全失代偿期临床研究，安徽中医学院学报，2009年12月第28卷第6期28-30.
[65]孔凡俊，中西医结合治疗早期糖尿病肾病50例临床观察，实用中西医结合临床2011年3月第11卷第2期.
[66]刘春倩，孟爱霞，黄吉峰，等．李显筑教授治疗糖尿病肾病经验[J]．长春中医药大学学报，2009，25（1）：10-11．
[67]韩吉祥，代清湘，常琼等，中西医联合治疗早期糖尿病肾病疗效观察，四川中医，2010年第28卷第4期.
[68]田素娟等．黄芪联合低分子肝素钙治疗老年性糖尿病肾病Ⅲ-Ⅳ期蛋白尿的疗效观察[J]．中华当代医学，2007，5(4):30．
[69]蒋忠华．葛根素注射液治疗50例早期糖尿病肾病疗效观察[J]．浙江临床医学，2007，7（9）：925．
[70]胥勋梅，夏芳，马勋龙，等．红花注射液治疗糖尿病肾病的疗效观察[J]．现代医药卫生，2007，23（7）：993-994．
[71]史伟，吴金玉，向彩春，等.水蛭注射液治疗糖尿病肾病57例[J].陕西中医，2007，28(4):401-403.
[72]杨彦，熊萍．川芎嗪注射液对23例糖尿病肾病患者血糖、尿蛋白及Ｃ反应蛋白的影响[J]．江苏中医药，2008，40（1）：34-35．
[73]魏玉菊，唐梅森.丹红注射液治疗糖尿病肾病的疗效观察[J].光明中医，2009，24(11):2112-2114.
[74]陈军宁，李作兴，韦广粤，等．银杏达莫注射液对早期糖尿病肾病炎性细胞因子的影响[J]．吉林医学，2010，31(22):3709-3710．
[75]郝玉杰，王运红，王桂英，等．肾康注射液对早期糖尿病肾病尿内皮素及血脂血黏度的影响[J]．河北医科大学学报，2010，31(2):136-138．
[76]田沛文，王静军，王雪琴.中西医结合治疗早期糖尿病肾病临床观察[J].山西中医，2008，24(8):24.
[77]朗江明，曹海伟，魏爱生，等.血栓通与血栓通与抵克立得治疗早期糖尿病肾的对比研究[J].中国中西医结合杂志，1998，18（12）：727-729.
[78]王文雄.苦碟子注射液治疗糖尿病肾病58例[J].药物与临床，2007，4（4）：135-136.
[79]姚春.丹参酮ⅡA注射液治疗早期糖尿病肾病的临床观察[J].现代医药卫生，2008，24(2):251.
[80]黄各宁，陈积优，张镁元.灯盏花素注射液对糖尿病肾病血液流变学影响的临床研究[J].新中医，2006，38(3):34-35.
[81]陆芝兰.刺五加注射液治疗早期糖尿病肾病64例临床观察[J].中医药导报，2007，13(7):40-41.
[82]赵宁，王鸣，费晓，等.参附注射液对早期DN血液D-D二聚体，Fib，CRP的影响[J].浙江中西医结合杂志，2007，17(8):476-478.
[83] Dalla vestra M, Masiero A, Roiter AM, et al. Is podocyte injury relevantin diabeticnephropathy studies in patients with type2diabetes [J].Diabetes,2003,52(4).
[84] Mundel P，ShanklandS J.Podocyte biology and response to injury[J].JAmSoc Nephrol，2002；13(12):3005-3015.
[85] LemleyKV，Abdullah I，Myers BD，Meyer TW，Blouch K，Smith WE，Bennet PH，Nelson RG.Evolution of incipient nephropathy in type2diabetes mellitus[J]. KidneyInt，2000，58:1228-1237.
[86] Pavenstadt H. Roles of the podocyte in glomerular function.[J] Am J Physiol RenalPhysiol.2000,278(2): F173-F179.
[87] Floege J，Alpers CE，Saqe EH，et al.Markers of complement-dependent andcomplement-independent glomerular visceral epithelial cell injury in vivo.Expression ofantiadhesive proteins and cytoskeletal ehanges.Lab Invest，1992:67(4):486-497.
[88] Wartio vaara J, Ofvrstedt LG, Khoshnoodi J, et al. Nephrin strands contribute to aporous slit diaphragm scaffold as revealed by electrontomography [J]. J Clin Invest,2004,114(7):1475-1483.
[89] Cooper ME, Mundel P, Boner G. Role of nephrin in renal disease including diabeticnephropathy.[J]. Semin Nephrol,2002,22(5):398.
[90] Caridi G, Perfumo F, Ghiggeri GM. NPHS2(Podocin) mutations in nephrotic syndrome.Clinical spectrum and fine mechanisms [J] Pediatr Res,2005,57(5Pt2):54R-61R.
[91] Huber TB, Schmidts M, Gerke P, etal. The carboxy termi-nus of Neph family membersbinds to the PDZ domain protein zonula occludens-1.[J] J Biol Chem,2003,278(15):13417-13421.
[92] Inoue T, Yaoita E, Kurihara H, etal. FAT is a comment ofglomeru-lar slit diaphragms.[J]Kidney Int,2001,59(3):1003-1012.
[93] Raats CJ, van den Born J, Bakker MA, et al. Expression of agrin, dystroglycan andutrophin in normal renal tissue and in experimental glomerulo pathies.Am JPathol,2000,156(5):1749-1765.
[94] Barisoni L，KoPP JB.Update in podocyte biology:putting one's，best foot forward. CurrOpin Nephrol Hypertens，2003;12(3):251-258.
[95] Takeda T，McQuistan T，Orlando RA，et al.Loss of glomerular foot processes isassociated with uncoupling of podocalyxin from the actin cytoskeleton.J Clin Invesr，2001，108:289-301.
[96] Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focalglomerulosclerosis.J Clin Invest，2001，108:1583-7.
[97] Kriz W, Gretz N，Lemley KV.Progression of glomerular diseases:is the podocyte theculprit [J].Kidney Int，1998，54(3):687-97.
[98] Xu ZG, Yoo TH, Ryu DR, et al. AngiotensinⅡreceptor blocker inhibits p27Kiplexpression in glucose-stimulated podocytes and in diabetic glomeruli. Kidney Int,2005,67(3):944-952.
[99] Petermann A, Hiromura K, Blonski M, et al. Mechanical stress reduces podocyteproliferation in vitro. Kidney Int,2002,61(1):40-50.
[100] Steffes MW, Schmidt D, Mccrery R, et al. Glomerular cell number in normal subjectsand in type1diabetic patients.[J] Kidney Int,2001,59(6):2104-2113.
[101]刘志红,李世军,陈朝红. DN患者足细胞病变的临床病理特征.[J]肾脏病透析与肾移植杂志,2003,12(2):144.
[102] Benigni A, Gagliardini E, Tomasoni S, et al. Selective mi-pairmentofgene expressionand assembly of nephrin in human diabetic nephropathy [J] Kidney Int,2004,65(6):2193-2200.
[103] Doublier S, Salvidio G, Lupia E, et al. Nephrin expression is reduced inhuman diabeticnephropathy: evidence for a distinct role for glycated albumin and angiotensinⅡ.[J]Diabetes,2003,52(4):1023-1030.
[104] Forbes JM, Bonnet F, Russo LM, t al. Modulation of nephrin in the diabetic kidney:association with systemic hypertension and increasing albuminuria. J Hypertens,2002,20(5):985-992.
[105] Toyoda M, Suzuki D, Umezono T, et al. Expression of human Nephrin mRNA indiabetic nephropathy.[J]. Nephrol Dial Transplant,2004,19(2):380-385.
[106] Chen HC, Chen CA, Guh JY, et al. Altering expression of alpha3beta1integrin onpodocytes of human and rats with Diabetes [J] Life Sci,2000,67(3):2345-2353.
[107] Blanco S, Vaquero M, Gomez-Guerrero C, et al. Potential role ofangiotensin-converting enzyme inhibitors and statins on early podocyte damage ina model of type2diabetes mellitus, obesity, andmild hypertension.[J] Am J Hypertens,2005,18(4):557-565.
[108]覃乔静，邓华聪，曹文富，等.血管紧张素II与糖尿病大鼠足细胞损害的实验研究[J].重庆医科大学学报，2004，29(4):448-451.
[109]吕智美,甘华.足细胞损伤与糖尿病[J].中华老年医学杂志,2005,24(1):67-71.
[110] Rincon-Choles H, Vasylyeva TL, Pergola PE, et al. ZO-1expression andphosphorylation in diabetic nephropathy [J].Diabetes,2006,55(4):894-900.
[111] Rincon-Choles H, Vasylyeva TL, Bhandari K, et al. Regulation of ZO-1expression andphosphorylation in experimental dia-betes. J Am Soc Nephrol,2003,14:47A.
[112] Cortes P,Mendez M，Riser BL，et al.F2actin fiber distribution in glomerular cells:structural and functional implications.Kidney Int，2000，58:2452.
[113] Siu B, Saha J, Smoyer WE, et al. Reduction in podocyte density as a pathologic featurein early diabetic nephropathy in rodents: prevention by lipoic acid treatment [J].BMCNephrol,2006,7:6.
[114] Dessapt C, Hargreaves R, Dei CA, et al. Modulation of alpha3-beta1integrinexpression and cell adhesion in glomerular podocytes by glucose and mechanicalstretch[J].Diabetic Med,2004,21(2):10-11.
[115] Koop K, Eikmans M, Baelde HJ, et al. Expression of podocyte associated molecules inacquired human kidney diseases. J Am Soc Nephrol,2003,14(8):2063-2071.
[116] Economou CG, Kitsiou PV, Tzina AK, et al. Enhanced podoca-lyxin expresing altersthe structure of podocyte basal surface. J Cell Sei,2004,117(Pt15):3281-3294.
[117] Nelson RG，Mmyer TW，Myers BD，et al.Clinical and pathological course of renaldisease innoninsulin-dependent diabetes mellitus: The Pima Indian experience，SeminNephrol，1997;17(2):124-131.
[118] Pagtaluma ME，Miller PL，Damping-Eagle S，et al.Podocyte Loss and ProgressiveGlomerular Injury in Type II Diabetes.J Clin Invest，1997;99(2):342-348.
[119] Kuusniemi AM，Merenmies J，Lahdenkari AT，et al. Glomerular sclerosis in kidneyswith congenital nephritic syndrome(NPHS1).Kidney Int，2006;70(8):1423-1431.
[120] Bariety J, Bruneval P, Meyrier A, et al. Podocyte involve-ment in human immunecrescentic glomerulonephritis [J]. Kidney Int,2005,68(3):109.
[121]吕智美，甘华.足细胞损伤与糖尿病[J].中华老年医学杂志.2005，24(l):67-71.
[122] Lee EY, Chung CH, Kim JH, et al. Antioxidants ameliorate the expression of vascularendothelial factor mediated by pro-tein kinase C in diabetic podocytes [J] Nephrol DialTrans-plant,2006,21(6):1496-1503.
[123] Benigni A, Tomasoni S, Gagliardini E, et al. Blocking angiotensin II synthesis/activitypreserves glomerular nephrin in rats with severe nephrosis [J] J Am SocNephrol,2001,12(3):941-948.
[124] Saleem MA, Ni L, Witherden I, et al. Co-localization of nephrin, podocin, and theactin cytoskeleton: evidence for a role in podocyte foot process formation. Am JPathol,2002,161(4):1459-1466.
[125] Toyoda M, Najafian B, Kmi Y, et al. Podocyte detachment and reduced glomerularcapillary endothelial fenestration in human type1diabetic nephropathy [J] Diabetes,2007,56(8):2155-2160.
[126] Okada T，Wada J，Hida K，et al. Thiazolidinediones arneliorate diabeticnephropathy via cell cycle-dependent mechanisms[J].Diabetes，2006，55(6):1666-1677.
[127] Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabeticnephropathy [J] Nephron Physiol,2007,106(2):26-31.
[128] Dessapt C, Hargreaves R, Dei CA, et al. Modulation of alpha3-beta1integrinexpression and cell adhesion in glomerular podocytes by glucose and mechanicalstretch[J].Diabetic Med,2004,21(2):10-11.
[129] Susztak K, Raff AC, Schiffer M, et al. Glucose-induced re-active oxygen species causeapoptosis of podocytes and podo-cyte depletion at the onset of diabetic nephropathy [J]Diabetes,2006,55(1):225-233.
[130] Kaplan JM, Kmi SH, North KN, et al. Mutations in ACTN4, encoding alpha-actinin-4,cause familial focal seg-mental glomerulosclerosis [J] NatGenet,2000,24(3):251-256.
[131] Baelde HJ, Eikmans M, Doran PP, et al. Gene expression profiling in glomeruli fromhuman kidneyswith diabetic ne-phropathy [J].Am J Kidney Dis,2004,43(4):
[132] Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glo-merulosclerosisand miplicates podocyte activation in the pathogenesis of diabetic nephropathy[J].Am JPathol，2003,162(4):1123-1137.
[133] Yoo TH, Li JJ, Kmi JJ, et al. Activation of the renin-angio-tensin system withinpodocytes in diabetes [J] Kidney Int,2007,71(10):1019-1027.
[134] Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabeticnephropathy [J] Nephron Physiol,2007,106(2):26-31.
[135] Iglesias-dela Cruz MC, Ziyadeh FN, Isono M, et al. Effects of high glucose and TGF-β1on the exp ression of collagen IV and vascular endothelial growth factor in mousepodocytes [J]. Kidney Int,2002,62(3):901-913.
[136] Cooper ME, Vranes D, Youssef S, et al. Increased renal expression of vascularendothelial growth factor (VEGF) and its receptor VEG-FR-2in experimental diabetes[J].Diabetes,1999,48(11):2229-2239.
[137] Chen S, Kasama Y, Lee JS,et al·Podocyte derived vascular endothelial growthfactormediates the stimulation of2α3(Ⅳ) collagen production by transforming growthfactor β1in mouse podocytes [J]·Diabetes,2004,53(11):2939-2949.
[138] Cummings E A, Sochett EB, Dekker MG, et al. Contribution of growth hormone andIGF-1to early diabetic nephropathy in type1diabetes. Diabetes,1998,47(8).
[139] Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovasculardisease in patients with type2diabetes[J].N Engl J Med,2003,348(5):383-393.
[140] Trelstad RL，Revel JP，Hay ED. Tight junctions between cells in the early chickelmbryo as visualized with the electron microscopy. The Joumal of cellbiology.1966Oct;31(1):C6-10.
[141] Hay RJ，Menzies RA，Morgan HP，Strehler BL.The division potential of cells incontinuous growth as compared to cells subcultivated after maintenance in stationaryphase.Experimental gerontology.1968Mar;3(1):35-44.
[142] Berardi R，Scartozzi M，Romagnoli E，Antognoli S，Cascinu S:Gastric cancertreatment: A systematic review.Oncol Rep2004;11:911-916.
[143] Pisani P，Bray F，Parkin DM:Estimates of the world-wide prevalence of cancer for25sites in the adult population.Int J Cancer2002:97:72-81.
[144] Ng YY，Huang TP，Yang WC，Chen ZP，Yang AH，Mu W，Nikolie-Paterson DJ，Atkins RC，Lan HY:Tubular epithelial-myofibroblast transdifferentiation in progressivetubulointerstitial fibrosis in5/6nephrectomized rats.Kidney Int1998;54:864-876.
[145] Ohkubo T，Ozawa M.The transcription factor Snail downregulates the tight junctioncomponents independently of E-cadherin downregulation[J].Cell Sci，2004，117(Ptg):1675-1685
[146] Jethwa P，Naquvi M，Hardy RG,et al.Overexpression of Slug is associated withmalignant progression of esophageal adenocarcinoma[J].World J Gastroentrol，2008，14(7):1044-1052.
[147] Reidy K, Susztak K. Epithelial-mesenchymal transition and podocyte loss in diabetickidney disease.Am J Kidney Dis,2009,54(4):590-593.
[148] Yam aguchi Y, Iwano M, Suzuki D, et al. Epithelial-mesenchymal transition as anexplanation for podocyte depletion in diabetic nephropathy.Am J Kidney D is,2009,54(4):653-664.
[149] Daisuke S,Yohei M,Tatsuyo N,et al.Amelioration of renal alterations in obese type2diabetic mice by vasohibin-1,a negative feedback regulator of angiogenesis.AJP-RenalPhysiol,2011,4:873-886.
[150] Li Y, Kang YS, Dai C,et al. Epithelial-to-mesenchymal transition is a potential pathwayleading to podocyte dysfunction and poteinuria[J].Am J Pathol,2008,172(2):299-308.
[151] Kang YS,Li Y,Dai C, et al.Inhibition of integrin-linked kinase blocks podocyteepithelial-mesenchymal transition and am eliorates proteinuri-a.Kidney Int,2010,78(4):363-373.
[152] Veeman MT,Axelrod JD,Moon RT.A second canon:functions and mechanisms ofbeta-catenin-independent Wnt signaling.Dev Cell,2003,5:367-377.
[153] Mariappan MM, Shetty M, Sataranatarajan K,et al.Glycogen synthase kinase3beta is anovel regulator of high glucose-and high insulin-induced extracellular matrix proteinsynthesis in renal proximal tubular epithelial cells.J Biol Chem,2008,283(45).
[154] Medici D,Hay ED,Olsen BR.Snail and Slug promote epithelial-mesenchymal transitionthrough beta-catenin-T-cell factor-4-dependent expression of transforming growthfactor-beta3.Mol BiolCell,2008,19(11):4875-87.
[155] Kim K, Lu Z,Hay ED.Direct evidence for a role of beta-catenin/LEF-1signalingpathway in induction of EMT.Cell Biol Int,2002,26(5):463-76.
[156] Jong In Yook,Xiao-Yan Li,Ichiro Ota,et al.Wnt-dependent regulation of the E-cadherinrepressor snail.J BiolChem,2005,280(12):11740-48.
[157] Coward RJ, Welsh GI, Yang J, et al. The human glomerular podocyte is a novel targetfor insulin action [J] Diebetes,2005,54(11):3095-3102.
[158] Nakamura T, Ushiyama C, Osada S, et al. Pioglitazone reduces urinary podocyteexcretion in type2diabetes patients with microal buminuria. Metabolish,2001,50(10):1193-1196.
[159] Kuhlmann A，Haas CS，Gross ML，et al.1,25-Dihydroxyvitamin D3decreases podocyteloss and podocyte hypertrophy in the subtotally nephrectomized rat [J].Am J physiolRenal Physiol，2004，286(3):F526-33.
[160] Wolf G, Chen S，Ziyadeh FN. From the periphery of the glomerular capillary walltoward the center of disease: podocyte injury comes of age in diabetic nephropathy,Diabetes，2005，54(6):1626-1634.
[161] Mifsud SA，Allen TJ，Bertram JF，et al.Podocyte foot process broadening inexperimental diabetic nephropathy:amelioration with renin-angiotensin blockade.Diabetologia，2001，44:878-82.
[162] Gross ML，EI-Shakmak A，Szabo A，et al.ACE-inhibitors but not endothelin receptorblockers prevent podocyte loss in early diabetic nephropathy.Diabetologia，2003，46.
[163] Gross ML，Ritz E，Schoof A，et al. Renal damage in the SHRI/N-cp type2diabetesmodel:comparison of an angiotensin-converting enzyme inhibitor and endothelinreceptor blocker[J].Lab Invest，2003，83(9):1267-77.
[164] Davis BJ, Cao Z, de Gaparo M, et al. Disparate effects of angiotensin Ⅱantagonistsand calcium channel blockers on albuminuria in experimental diabetes andhypertension: potential role of nephrin.[J].J Hypertens,2003,21(1):209-16.
[165]魏洪坤，方敬爱，孙艳艳，等.肾炎康复片对糖尿病肾病大鼠肾组织podocalyxin表达的影响[J].中国中西医结合肾病杂志，2009,10（6）：485-488.
[166]陈姝君，陈海平，刘奇.尿毒清颗粒对糖尿病大鼠足细胞损伤的保护作用研究[J].中国中西医结合肾病杂志，2008,9（10）：875-878.
[167] Zhang P, Zhang J J, Su J, et al. Effect of total glucosides of paeony on the expression ofnephrin in the kidneys from diabetic rats[J]. Am J ChinMed,2009,37(2):295.
[168]许洪燕，方敬爱，张晓东，等.益肾胶囊对糖尿病肾病模型肾小球足细胞的影响[J].中国中西医结合肾病杂志,2009，10(7):577.
[169] Wolf G，Chen S，Ziyadeh FN. From the periphery of the glomerular capillary walltoward the center of disease：pocyte injury comes of age in diabeticnephropathy[J].Diabetes，2005，54：1626-1634.
[170]仝小林.糖尿病中医防治指南解读[M].北京：中国中医药出版社，2009:55.
[171]陈灏珠．实用内科学:七册［M］．12版．北京:人民卫生出版社，2005:1015.
[172]任继学，任继学经验集．北京：人民卫生出版社，2009.
[173] Durvasu la RV，Shank land SJ. Podocyte injury and targeting therapy an update CurrOpin Nehprol Hypertena，2006，15(1):1-7.
[174] Lin CL，Wang JY，Huang YT，et al. Wnt/beta-catenin signaling modulates survival ofhigh glucose-stressed mesangial cells.J Am Soc Nephrol，2006，17:2812-20.
[175] Dai C.，Stolz D.B.，Kiss L.P.，et al. Wnt/beta-catenin signaling promotes podocytedysfunction and albuminuria.J.Am.Soc.Nephrol.,2009,20:1997-2008.
[176] ZHA Yun Hong，MEI YuanWu，MAO Ling.The Advantages for Snail Expression toPromote Cell Migration and Induce Actin Reorganization and to Protect Against theSerum deprivation triggered Apoptosis of Bone Marrow Stem Cells.Journal ofBiotechnology.2007,23(4)645-651.
[177] Miyoshi A，Kitajima Y，Sumi K，et al.Snail and SIPI increase cancer invasion byupregulation MMP family in hepatocellular carcinoma cell.Br JCancer.2004,90:1265-1273.
[178] Yokoyama K，Kamata N，Fujimoto R，et al.Increased invasion and matrixmetalloproteinase-2expression by Snail-induced mesenchymal transition in squamouscell carcinomas.Int J Oncol.2003,22(4):891.
[179] Brunner F P，Thiel G，Hermle M，et al.Long-term enalapril and verapamil in rats withreduced renal mass.Kidney Int.1989.36(6):969-977.