解毒通络保肾胶嚢干预实验性糖尿病大鼠肾脏氧化应激机制及与脂联素关系的研究
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摘要
目的:糖尿病肾病（diabetic nephropathy， DN）是临床最常见、多发的糖尿病（diabetes mellitus，DM）并发症。是DM最严重的微血管并发症，主要表现为以微血管损害为主的肾小球病变。主要病理表现为毛细血管基底膜通透性增加、基底膜增厚、肾小球系膜区细胞外基质（extracellular matrix， ECM）积聚，日久发展为肾小球硬化，终至肾纤维化。临床上早期主要表现为肾小球肥大，肾小球高滤过状态，继而出现为微量蛋白尿，持续蛋白尿、水肿、高血压、逐渐发展为肾功能不全，终至肾衰竭。DN病因及发病机制错综复杂，目前认为其发生、发展是由于多因素、多途径综合作用的结果。目前现代医学治疗手段主要以降血糖、血压，保护肾功能，延缓DN发生发展。但是目前尚缺乏有效的预防和治疗手段，大部分患者逐渐发展至肾衰竭而危及生命。
近年来关于DN发病机制的学说中，氧化应激成为糖尿病肾病发病机制的焦点。为抗氧化治疗在DN中的应用提供了理论基础。从脂联素发现以来，诸多研究证实脂联素与DM及DN的关系密切，脂联素不仅有抗炎、抗动脉硬化作用，而且还具有抗氧化作用，脂联素水平的降低可能引起抑制AMPK激活，从而抑制AMPK活化eNOS，引起NO减少，而ROS增加，在肾脏中ECM的聚集增加而引起DN。脂联素可能参与调控DN的氧化应激机制。
方法:本实验对解毒通络保肾胶囊防治DN进行较系统的研究。重点探讨毒损肾络病机理论与氧化应激机制的关系，以及解毒通络保肾胶囊干预DN的氧化应激发病机制及与脂联素的关系，论证解毒通络保肾胶囊治疗DN的独特优势，进一步证明解毒通络保肾法的科学性，从毒损肾络、氧化应激、脂联素新的角度阐明DN的发病机制。
本实验研究通过解毒通络保肾胶囊干预实验性糖尿病大鼠肾脏氧化应激机制的研究，探讨解毒通络保肾胶囊对实验性糖尿病大鼠肾脏保护的作用机制及与脂联素的关系，为中医药防治DN提供更为完善的理论及实验依据。本实验研究分为四个部分：
1采用高脂饲养结合链脲佐菌素（STZ）复制实验性2型DM大鼠模型，按实验需要分为DM模型组、阳性对照组和中药实验组，并设正常对照组。实验过程中密切观察糖尿病大鼠的一般状态；运用酶联免疫吸附法、生物化学等实验技术，检测血生化指标、胰岛素测定、尿微量白蛋白等，研究解毒通络保肾胶囊对实验性糖尿病大鼠肾脏的保护作用；
2采用免疫组化学法检测纤维连接蛋白（FN）和IV型胶原（Col IV）变化，观察解毒通络保肾胶囊对实验性DM大鼠肾小球系膜区细胞外基质（ECM）积聚的影响；采用光镜、透射电镜观察实验性DM大鼠肾组织病理形态学变化情况；
3采用免疫组织化学法、双抗体夹心酶联免疫吸附法（ELISA）、荧光实时定量PCR等实验技术，观察解毒通络保肾胶囊对DM大鼠血清ADPN、肾组织ADPN、磷酸化腺苷酸蛋白活化激酶（p-AMPK）及内皮型一氧化氮酶（eNOS）的蛋白表达、肾组织AdipoR1、AdipoR2和eNOS的基因表达的影响；
4采用ELISA技术，观察解毒通络保肾胶囊对大鼠肾组中活性氧（ROS）、8-羟基脱氧鸟苷（8-OHdG）、3-硝基酪氮酸（3-NT）蛋白及基因表达的影响。
结果:
1解毒通络保肾胶囊能改善实验性DM大鼠的一般状态，具有一定的降血糖、改善胰岛素水平及调节血脂异常的作用；
2解毒通络保肾胶囊能抑制实验性DM大鼠早期肾脏肥大及肾小球高滤过状态，减少尿微量白蛋白的排出，具有一定的保护肾功能的作用；
3解毒通络保肾胶囊具有抑制实验性DM大鼠肾脏的病理组织形态学及超微结构的改变，减少肾组织的FN及Col IV的表达，减少肾小球系膜区细胞外基质的积聚的作用，从而减轻DM性肾小球硬化，防止肾纤维化，延缓DN的发生发展；
4解毒通络保肾胶囊具有增加DM大鼠血清ADPN的含量、上调肾组织ADPN蛋白的表达及肾组织AdipoR1、AdipoR2基因表达的作用，且AdipoR1的表达高于AdipoR2表达；
5解毒通络保肾胶囊具有增加肾组织中p-AMPK的蛋白的表达，同时eNOS基因及蛋白的表达，与脂联素水平的呈正相关。提示脂联素水平增加，可能增强活化AMPK表达上调，AMPK激活eNOS的表达上调。
6高脂饲养结合STZ造模的DM大鼠肾组织中ROS、8-OHdG、3-NT的含量增加，提示肾脏氧化应激在DN发病机制中起重要作用。肾组织中ROS、8-OHdG、3-NT的含量增加，与血清ADPN水平及肾脏组织中ADPN表达水平呈负相关，表明DN肾脏氧化应激发病与ADPN有一定的关联。
7解毒通络保肾胶囊能明显抑制DM大鼠肾组织ROS、8-OHdG及3-NT的含量，其抑制氧化应激发病机制可能是通过增加ADPN水平，增强AMPK活化，AMPK又激活eNOS的表达上调，从而减少ROS、8-OHdG、3-NT的表达，增加NO的表达，起到一定的保护肾组织的作用。
结论:本实验研究结果说明，解毒通络保肾胶囊能降低实验性糖尿病大鼠的血糖，增加胰岛素水平，调节血脂异常，保护肾功能，增加DM大鼠血清ADPN水平、肾组织中ADPN蛋白及基因表达，减少肾组织中ROS、8-OHdG、3-NT等含量，抑制DM大鼠肾脏氧化应激反应，从而减轻肾组织的损害，延缓DM发展。
本实验研究的创新点是完善解毒通络保肾治法学说，将DN氧化应激机制引入该治法的研究中，探讨ADPN及其受体系统调控DN氧化应激发病机制与中医毒损肾络病机理论的关系；将ADPN及其受体系统调控氧化应激机制应用于DN的研究是一种崭新的设想，可能成为防治DN的新靶点，为解毒通络保肾胶囊防治DN提供了新的思路和实验依据。
Propose:Diabetic nephropathy （called DN for short） is not only the most common andmultiple clinical diabetes mellitus （called DM for short） complications， but also the mostserious microvascular complications. DN contributes to glomerulopathy of mainlymicrovascular damage. The main pathology shows it increases the permeability of capillarybasement membrane， increases the thick of basement membrane， and accumulatesglomerular mesangial extracellular matrix （called ECM for short）.These changes makeglomerulosclerosis， and eventually it becomes renal fibrosis. The early clinicalperformance is glomerular hypertrophy， glomerular hyper-filterability;the following changeis micro-albuminuria， persistent proteinuria， edema， hypertension;finally it cause toprogressive development of renal insufficiency， and to renal failure at last. The etiology andpathogenesis of DN is complex and due to the multiple factors and ways. Presently themedical treatment is reducing blood sugar， reducing blood pressure， and protecting renalfunction to delay DN progression. But there is a lack of effective means of prevention andtreatment， and most patients gradually developed into renal failure and life-threatening.
In recent years， the theory of oxidative stress in DN pathogenesis becomes the focustheory， which provides a theoretical basis for antioxidant therapy in the DN. Since thediscovery of adiponectin， many studies confirmed that adiponectin is closely related to DMand DN. Adiponectin is not only anti-inflammatory， anti-atherogenic effect， but also hasantioxidant properties. The reduced adiponectin levels may lead to inhibit AMPK activation，thus inhibit AMPK activating to eNOS， cause NO reducing and ROS increasing，. Thesefactors cause the aggregation of ECM in the kidney，which cause to DN. Adiponectin mayregulate the oxidative stress mechanism.
Methods:This experiment about the Chinese herbal medicine jie du tong luo bao shencapsule（called JJTLBS capsule for short） of prevention DN has been studied systematically.The emphasis is to discuss the relationship between poison damage kidney networkpathogenesis theory and oxidative stress， JJTLBS capsule and adiponectin， and todemonstrate the unique advantage of JJTLBS capsule in the treatment of DN. It also confirmsthe scientific nature of the treatment of detoxification， deoppilation meridian and securitykidney， clarify the pathogenesis of DN from the toxic damage to the kidney， oxidative stress， and adiponectin.
This experiment explores protection mechanism of JJTLBS capsule towardsexperimental diabetic rat kidney， and relationship between mechanism and adiponectin bystudying the kidney oxidative stress mechanisms about JJTLBS capsule interfered theexperimental diabetic rat. The experiment also provide more comprehensive theoretical andexperimental basis to prevent and treat of DN to. The experiment is divided into four parts:
1The experimental type2DM rat model was made with high-fat diet combined withstreptozotocin （called STZ for short）. These models divided into the DM model group， thepositive control group， the experimental group and normal control group. Close observe thegeneral state of the diabetic rats.Detect blood biochemical indices， urine albumin， insulindetermination using enzyme-linked immunosorbent assay， biochemistry and otherexperimental techniques for studying protective effects of JJTLBS capsule towardsexperimental diabetic rat kidney，
2Detect fibronectin protein （FN） and type IV collagen （Col IV） by using theImmunohistochemistry assay in order to observe the ECM accumulation of JJTLBS capsuletowards experimental diabetic rat kidney. Observe the morphological changes of renal tissueby using light microscopy and transmission electron microscopy.
3Detect protein expression of ADPN in serum and renal tissues， phosphorylationadenylate protein-activated protein kinase（p-AMPK），and endothelial nitric oxide enzymes（eNOS）; gene expression of AdipoR1， AdipoR2and eNOS in renal tissue by using doubleantibody sandwich enzyme-linked immunosorbent assay（ELISA），immunohistochemistry，and fluorescence real-time quantitative PCR experiments to observe JJTLBS capsule towardsexperimental diabetic rat kidney.
4Detect protein and gene expression of reactive oxygen species （ROS），8-hydroxy-deoxy guanosine （8-OHdG），3-nitro-casein nitrogen （3-NT） in renal tissuesby using ELISA technique to observe JJTLBS capsule towards experimental diabetic ratkidney.
Results:
1JJTLBS capsules can improve the general state of the experimental DM rats，decrease blood sugar， improve insulin levels and regulate dyslipidemia.
2JJTLBS capsules can inhibit early renal hypertrophy and glomerular hyper-filtration state of the experimental DM rats，decrease urinary albumin excretion，which would protectrenal function.
3JJTLBS capsules can inhibit the experimental DM rats morphological andultrastructural changes of rat kidney histopathology， decrease the expression of FN and ColIV in the renal tissue， decrease the ECM accumulation， which would reduce the DMglomerular sclerosis， prevent the renal fibrosis， delay the occurrence and development ofthe DN.
4JJTLBS capsules can increase the serum adiponectin levels， adiponectin proteinexpression in renal tissue， AdipoR1， AdipoR2gene expression in renal tissue. While theexpression levels of AdipoR1is higher than AdipoR2.
5JJTLBS capsules can increase p-AMPK protein expression in renal tissue. The geneand protein expression of eNOS were positively correlated towards adiponectin levels. Itconfirms that the increasing of adiponectin levels may enhance up-regulation the activation ofAMPK， while the AMPK active the up-regulation of eNOS.
6the increased content of ROS，8-OHdG， and3-NT in the experimental DM ratssuggest that oxidative stress in kidneys play an important role in DN pathogenesis. Thecontent of ROS，8-OHdG and3-NT in kidney tissue is increased， which shows negativelycorrelated towards adiponectin levels in serum and kidney tissue. The results above showsthat the DN renal oxidative stress and adiponectin is known as the association.
7JJTLBS capsules can obviously inhibit the kidney tissue content of ROS，8-OHdGand3-NT in the experimental DM rats. The pathogenesis of oxidative stress may perform likethis: it increased adiponectin levels，enhanced AMPK activation，and the activated AMPKmade the up-regulation of eNOS. Therefore， the expression of8-OHdG and3-NT werereduced and the expression of NO increased， which play a role in the protection kidneytissue.
Conclusion:These results suggest that JJTLBS capsule can reduce the experimental DMrats blood glucose，increase insulin levels，regulate dyslipidemia and protect renal function，increased serum adiponectin levels， the protein and gene expression of adiponectin in renaltissue， reduce the content of ROS，8-OHdG and3-NT in renal tissue， and inhibit oxidativestress. Thus it would abatement the renal tissue damage， delay the DM development.
The innovation of this experimental study is to improve the theory of detoxification， deoppilation meridian and security kidney， and introduce DN oxidative stress mechanism init. This experiment explore the relationship between DN oxidative stress in the pathogenesis，regulated by adiponectin and its receptors， and the TCM toxickidney by the theory ofpathogenesis. DN oxidative stress mechanism regulated by adiponectin and its receptors is anew idea，which may become a new target for treatment of DN，and provides new ideas andexperimental evidence when applying JJTLBS capsule for curing DN.
近年来关于DN发病机制的学说中，氧化应激成为糖尿病肾病发病机制的焦点。为抗氧化治疗在DN中的应用提供了理论基础。从脂联素发现以来，诸多研究证实脂联素与DM及DN的关系密切，脂联素不仅有抗炎、抗动脉硬化作用，而且还具有抗氧化作用，脂联素水平的降低可能引起抑制AMPK激活，从而抑制AMPK活化eNOS，引起NO减少，而ROS增加，在肾脏中ECM的聚集增加而引起DN。脂联素可能参与调控DN的氧化应激机制。
方法:本实验对解毒通络保肾胶囊防治DN进行较系统的研究。重点探讨毒损肾络病机理论与氧化应激机制的关系，以及解毒通络保肾胶囊干预DN的氧化应激发病机制及与脂联素的关系，论证解毒通络保肾胶囊治疗DN的独特优势，进一步证明解毒通络保肾法的科学性，从毒损肾络、氧化应激、脂联素新的角度阐明DN的发病机制。
本实验研究通过解毒通络保肾胶囊干预实验性糖尿病大鼠肾脏氧化应激机制的研究，探讨解毒通络保肾胶囊对实验性糖尿病大鼠肾脏保护的作用机制及与脂联素的关系，为中医药防治DN提供更为完善的理论及实验依据。本实验研究分为四个部分：
1采用高脂饲养结合链脲佐菌素（STZ）复制实验性2型DM大鼠模型，按实验需要分为DM模型组、阳性对照组和中药实验组，并设正常对照组。实验过程中密切观察糖尿病大鼠的一般状态；运用酶联免疫吸附法、生物化学等实验技术，检测血生化指标、胰岛素测定、尿微量白蛋白等，研究解毒通络保肾胶囊对实验性糖尿病大鼠肾脏的保护作用；
2采用免疫组化学法检测纤维连接蛋白（FN）和IV型胶原（Col IV）变化，观察解毒通络保肾胶囊对实验性DM大鼠肾小球系膜区细胞外基质（ECM）积聚的影响；采用光镜、透射电镜观察实验性DM大鼠肾组织病理形态学变化情况；
3采用免疫组织化学法、双抗体夹心酶联免疫吸附法（ELISA）、荧光实时定量PCR等实验技术，观察解毒通络保肾胶囊对DM大鼠血清ADPN、肾组织ADPN、磷酸化腺苷酸蛋白活化激酶（p-AMPK）及内皮型一氧化氮酶（eNOS）的蛋白表达、肾组织AdipoR1、AdipoR2和eNOS的基因表达的影响；
4采用ELISA技术，观察解毒通络保肾胶囊对大鼠肾组中活性氧（ROS）、8-羟基脱氧鸟苷（8-OHdG）、3-硝基酪氮酸（3-NT）蛋白及基因表达的影响。
结果:
1解毒通络保肾胶囊能改善实验性DM大鼠的一般状态，具有一定的降血糖、改善胰岛素水平及调节血脂异常的作用；
2解毒通络保肾胶囊能抑制实验性DM大鼠早期肾脏肥大及肾小球高滤过状态，减少尿微量白蛋白的排出，具有一定的保护肾功能的作用；
3解毒通络保肾胶囊具有抑制实验性DM大鼠肾脏的病理组织形态学及超微结构的改变，减少肾组织的FN及Col IV的表达，减少肾小球系膜区细胞外基质的积聚的作用，从而减轻DM性肾小球硬化，防止肾纤维化，延缓DN的发生发展；
4解毒通络保肾胶囊具有增加DM大鼠血清ADPN的含量、上调肾组织ADPN蛋白的表达及肾组织AdipoR1、AdipoR2基因表达的作用，且AdipoR1的表达高于AdipoR2表达；
5解毒通络保肾胶囊具有增加肾组织中p-AMPK的蛋白的表达，同时eNOS基因及蛋白的表达，与脂联素水平的呈正相关。提示脂联素水平增加，可能增强活化AMPK表达上调，AMPK激活eNOS的表达上调。
6高脂饲养结合STZ造模的DM大鼠肾组织中ROS、8-OHdG、3-NT的含量增加，提示肾脏氧化应激在DN发病机制中起重要作用。肾组织中ROS、8-OHdG、3-NT的含量增加，与血清ADPN水平及肾脏组织中ADPN表达水平呈负相关，表明DN肾脏氧化应激发病与ADPN有一定的关联。
7解毒通络保肾胶囊能明显抑制DM大鼠肾组织ROS、8-OHdG及3-NT的含量，其抑制氧化应激发病机制可能是通过增加ADPN水平，增强AMPK活化，AMPK又激活eNOS的表达上调，从而减少ROS、8-OHdG、3-NT的表达，增加NO的表达，起到一定的保护肾组织的作用。
结论:本实验研究结果说明，解毒通络保肾胶囊能降低实验性糖尿病大鼠的血糖，增加胰岛素水平，调节血脂异常，保护肾功能，增加DM大鼠血清ADPN水平、肾组织中ADPN蛋白及基因表达，减少肾组织中ROS、8-OHdG、3-NT等含量，抑制DM大鼠肾脏氧化应激反应，从而减轻肾组织的损害，延缓DM发展。
本实验研究的创新点是完善解毒通络保肾治法学说，将DN氧化应激机制引入该治法的研究中，探讨ADPN及其受体系统调控DN氧化应激发病机制与中医毒损肾络病机理论的关系；将ADPN及其受体系统调控氧化应激机制应用于DN的研究是一种崭新的设想，可能成为防治DN的新靶点，为解毒通络保肾胶囊防治DN提供了新的思路和实验依据。
Propose:Diabetic nephropathy （called DN for short） is not only the most common andmultiple clinical diabetes mellitus （called DM for short） complications， but also the mostserious microvascular complications. DN contributes to glomerulopathy of mainlymicrovascular damage. The main pathology shows it increases the permeability of capillarybasement membrane， increases the thick of basement membrane， and accumulatesglomerular mesangial extracellular matrix （called ECM for short）.These changes makeglomerulosclerosis， and eventually it becomes renal fibrosis. The early clinicalperformance is glomerular hypertrophy， glomerular hyper-filterability;the following changeis micro-albuminuria， persistent proteinuria， edema， hypertension;finally it cause toprogressive development of renal insufficiency， and to renal failure at last. The etiology andpathogenesis of DN is complex and due to the multiple factors and ways. Presently themedical treatment is reducing blood sugar， reducing blood pressure， and protecting renalfunction to delay DN progression. But there is a lack of effective means of prevention andtreatment， and most patients gradually developed into renal failure and life-threatening.
In recent years， the theory of oxidative stress in DN pathogenesis becomes the focustheory， which provides a theoretical basis for antioxidant therapy in the DN. Since thediscovery of adiponectin， many studies confirmed that adiponectin is closely related to DMand DN. Adiponectin is not only anti-inflammatory， anti-atherogenic effect， but also hasantioxidant properties. The reduced adiponectin levels may lead to inhibit AMPK activation，thus inhibit AMPK activating to eNOS， cause NO reducing and ROS increasing，. Thesefactors cause the aggregation of ECM in the kidney，which cause to DN. Adiponectin mayregulate the oxidative stress mechanism.
Methods:This experiment about the Chinese herbal medicine jie du tong luo bao shencapsule（called JJTLBS capsule for short） of prevention DN has been studied systematically.The emphasis is to discuss the relationship between poison damage kidney networkpathogenesis theory and oxidative stress， JJTLBS capsule and adiponectin， and todemonstrate the unique advantage of JJTLBS capsule in the treatment of DN. It also confirmsthe scientific nature of the treatment of detoxification， deoppilation meridian and securitykidney， clarify the pathogenesis of DN from the toxic damage to the kidney， oxidative stress， and adiponectin.
This experiment explores protection mechanism of JJTLBS capsule towardsexperimental diabetic rat kidney， and relationship between mechanism and adiponectin bystudying the kidney oxidative stress mechanisms about JJTLBS capsule interfered theexperimental diabetic rat. The experiment also provide more comprehensive theoretical andexperimental basis to prevent and treat of DN to. The experiment is divided into four parts:
1The experimental type2DM rat model was made with high-fat diet combined withstreptozotocin （called STZ for short）. These models divided into the DM model group， thepositive control group， the experimental group and normal control group. Close observe thegeneral state of the diabetic rats.Detect blood biochemical indices， urine albumin， insulindetermination using enzyme-linked immunosorbent assay， biochemistry and otherexperimental techniques for studying protective effects of JJTLBS capsule towardsexperimental diabetic rat kidney，
2Detect fibronectin protein （FN） and type IV collagen （Col IV） by using theImmunohistochemistry assay in order to observe the ECM accumulation of JJTLBS capsuletowards experimental diabetic rat kidney. Observe the morphological changes of renal tissueby using light microscopy and transmission electron microscopy.
3Detect protein expression of ADPN in serum and renal tissues， phosphorylationadenylate protein-activated protein kinase（p-AMPK），and endothelial nitric oxide enzymes（eNOS）; gene expression of AdipoR1， AdipoR2and eNOS in renal tissue by using doubleantibody sandwich enzyme-linked immunosorbent assay（ELISA），immunohistochemistry，and fluorescence real-time quantitative PCR experiments to observe JJTLBS capsule towardsexperimental diabetic rat kidney.
4Detect protein and gene expression of reactive oxygen species （ROS），8-hydroxy-deoxy guanosine （8-OHdG），3-nitro-casein nitrogen （3-NT） in renal tissuesby using ELISA technique to observe JJTLBS capsule towards experimental diabetic ratkidney.
Results:
1JJTLBS capsules can improve the general state of the experimental DM rats，decrease blood sugar， improve insulin levels and regulate dyslipidemia.
2JJTLBS capsules can inhibit early renal hypertrophy and glomerular hyper-filtration state of the experimental DM rats，decrease urinary albumin excretion，which would protectrenal function.
3JJTLBS capsules can inhibit the experimental DM rats morphological andultrastructural changes of rat kidney histopathology， decrease the expression of FN and ColIV in the renal tissue， decrease the ECM accumulation， which would reduce the DMglomerular sclerosis， prevent the renal fibrosis， delay the occurrence and development ofthe DN.
4JJTLBS capsules can increase the serum adiponectin levels， adiponectin proteinexpression in renal tissue， AdipoR1， AdipoR2gene expression in renal tissue. While theexpression levels of AdipoR1is higher than AdipoR2.
5JJTLBS capsules can increase p-AMPK protein expression in renal tissue. The geneand protein expression of eNOS were positively correlated towards adiponectin levels. Itconfirms that the increasing of adiponectin levels may enhance up-regulation the activation ofAMPK， while the AMPK active the up-regulation of eNOS.
6the increased content of ROS，8-OHdG， and3-NT in the experimental DM ratssuggest that oxidative stress in kidneys play an important role in DN pathogenesis. Thecontent of ROS，8-OHdG and3-NT in kidney tissue is increased， which shows negativelycorrelated towards adiponectin levels in serum and kidney tissue. The results above showsthat the DN renal oxidative stress and adiponectin is known as the association.
7JJTLBS capsules can obviously inhibit the kidney tissue content of ROS，8-OHdGand3-NT in the experimental DM rats. The pathogenesis of oxidative stress may perform likethis: it increased adiponectin levels，enhanced AMPK activation，and the activated AMPKmade the up-regulation of eNOS. Therefore， the expression of8-OHdG and3-NT werereduced and the expression of NO increased， which play a role in the protection kidneytissue.
Conclusion:These results suggest that JJTLBS capsule can reduce the experimental DMrats blood glucose，increase insulin levels，regulate dyslipidemia and protect renal function，increased serum adiponectin levels， the protein and gene expression of adiponectin in renaltissue， reduce the content of ROS，8-OHdG and3-NT in renal tissue， and inhibit oxidativestress. Thus it would abatement the renal tissue damage， delay the DM development.
The innovation of this experimental study is to improve the theory of detoxification， deoppilation meridian and security kidney， and introduce DN oxidative stress mechanism init. This experiment explore the relationship between DN oxidative stress in the pathogenesis，regulated by adiponectin and its receptors， and the TCM toxickidney by the theory ofpathogenesis. DN oxidative stress mechanism regulated by adiponectin and its receptors is anew idea，which may become a new target for treatment of DN，and provides new ideas andexperimental evidence when applying JJTLBS capsule for curing DN.
引文
[1]吕仁和，赵进喜，王越.糖尿病肾病临床研究述评.北京中医药大学学报,1994,7(2)2.
[2]林兰.治疗糖尿病肾病的经验[J].辽宁中医杂志,2000,27(4):145
[3]南征.消渴肾病(糖尿病肾病)研究[M].第一版.长春.吉林科学技术出版社,2001,5:1-5.
[4]任继学.任继学经验集.第一版.北京.人民卫生出版社出版,2000,195-197.
[5]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[J].中国中西医结合肾病,2005,6(5):253-254
[6]封翠云.糖尿病肾病的中医病名探讨[J].国医论坛,2007,22(2):22
[7]林兰.中西医结合糖尿病学[M］.北京：中国医药科技出版社,1999：395-407.
[8]张先闻.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.
[9]郭向东,王小琴,熊玮．中西医结合治疗早期糖尿病肾病33例观察[J］．实用中医药杂志,2008,1,1(24):24－25．
[10]贺学林.陈以平教授治疗临床经验[J].中国中西医结合肾病杂志,2000,1(1):7-8.
[11]吴以岭,魏聪,贾振华．从络病学说探讨糖尿病肾病的病机[J］．中国中医基础医学杂志,2007,13(9):590－591
[12]赵会贤,苏荣华.DN的病因病机及证治浅识[J].中医药学刊.2004,9:1760-1761.
[13]李琪,高阳,刘启庭.糖肾康治疗2型DN的临床研究[J].辽宁中医杂志,1998,(3):114-116.
[14]吕仁和,赵进喜,王世东.糖尿病及其并发症的临床研究.新中医,2001,33(3):4
[15]张岩．糖尿病肾病的中医病因病机浅析[J］．光明中医,2010(3):406－407.
[16]陈筱云,赵丽娟.从瘀论治糖尿病肾病[J].中国中医基础医学杂志,2002,8(7):53-54
[17]方水林．糖尿病肾病从瘀论治探讨[J］．实用中医内科杂志,2006,20(6):606－607．
[18]李小会,董正华.糖尿病肾病病因病机探讨[J].陕西中医,2005,26(6):552-553
[19]宋述菊,牟宗秀.糖尿病肾病病因病机及辨治探讨.山东中医杂志,1999,18(4):147-148
[20]邱晓堂．张永杰教授从脾论治糖尿病肾病[J］．河南中医,2005,25(1):26－27
[21]范晔,莫传伟,陈群,等．糖尿病肾病五脏相关研究[J］．安徽中医学院学报,2008,27(1):17－18．
[22]张彤.叶景华治疗糖尿病肾病经验[J］.中医杂志,2003(10)：734-735.
[23]王秀珍.健脾固肾汤治疗早期糖尿病肾病40例[J].浙江中医杂志,2004,(6):332
[24]杨文军,赵孔华.脾肾气机升降失常与糖尿病肾病关系探讨[J］.山东中医药大学学报,2005,29(3)：188-189.
[25]李俊美.吕仁和教授治疗糖尿病肾病的经验[J］.四川中医,2009,27(5)：1-3.
[26]丁英钧,肖永华,傅强,潘莉,赵进喜.糖尿病肾病“微型癥瘕”病理假说解析[J].中华中医药杂志,2009,24(1)：27-28
[27]南征.毒损肾络所致消渴肾病机理浅说[J].吉林中医药,2007,27(2):11
[28]于敏,张波,史耀勋,南征.南征教授“毒损肾络”理论学说探析及临床运用[J].中华中医药学刊,2010,28(2)：244-245
[29]曹和欣,何立群.糖肾宁对早期糖尿病肾病大鼠高滤过的影响[J］.上海中医药杂志,2001,35(5)：19-21.
[30]周晖.高彦彬教授诊治糖尿病肾病的临床经验[J］.辽宁中医杂志,2009,36(7)：1078-1079.
[31]魏军平,林兰·中西医结合治疗糖尿病研究进展[J]·医学研究杂志,2007,36(4):16-19.
[32]吕仁和,赵进喜,王世东.糖尿病及其并发症的临床研究[J].新中医,2001,33(3)：4
[33]詹锐文.糖尿病肾病析义[J].辽宁中医杂志,2004,31(7):566-567.
[34]王耀献,王翚.糖尿病肾病的中医分型辨证论治[J］.糖尿病新世界,2005,8(4)：22.
[35]肖永华.吕仁和治疗糖尿病肾病经验[J].世界中医药,2007,2(3)：151-153.
[36]魏军平,林兰.糖尿病肾病的辨治经验[J].国际中医中药杂志,2007,29(3):177-178.
[37]韩云平．李小娟教授治疗糖尿病肾病经验撷要[J］．实用中医内科杂志,2009,23(1):13－14．
[38]徐延.中西医结合治疗糖尿病肾病33例[J］.四川中医,2002,20(6)：38-39.
[39]李朝晖.中西医结合治疗糖尿病肾病临床观察[J].河北中医,2005,27(2)：122－123.
[40]王小光,王亚丽,张佩清.张琪教授辨治糖尿病肾病经验介绍[J］.新中医,2005,37(3)：20-21.
[41]叶任高.中西医结合肾脏病学[M].北京:人民卫生出版社,2003:305-307.
[42]吕贵德.辨证论治糖尿病肾病38例疗效观察[J].河北中医,2002,24(2):103-104.
[43]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)：42-43.
[44]赵东鹰.辨证论治结合西药治疗糖尿病肾病56例[J].陕西中医,2007,28(4):415-416
[45]吴以岭,魏聪,贾振华,朱昭明.从络病病学说论治糖尿病肾病[J].疑难病杂志,2007,6(6):350-351.
[46]李桂芝,郑万发.中医辨证治疗糖尿病肾病100例疗效观察.云南中医中药杂志,2007,28(1):17
[47]林兰,倪青,高齐健,等.糖微康胶囊治疗糖尿病肾病的临床观察[J].中国中西医结合杂志,2000,20(11):811-814
[48]高彦彬,赵慧玲,关崧等.糖肾宁治疗气阴两虚、络脉瘀滞型早期糖尿病肾病临床研究[J].中华中医药杂志,2006,21(7):409-411
[49]董正华,曹广顺,曹雯,等.通络益肾汤治疗糖尿病肾病30例[J].上海中医药杂志,2007,41(9),46-48.
[50]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.
[51]李亚文,杨焱,陈凤娇,陈化龙.血府逐瘀汤加减治疗糖尿病肾病40例临床观察[J].中国现代药物应用,2009,3(3):95-96
[52]刘建平.参芪益肾汤治疗早期糖尿病肾病35例疗效观察[J].中国医药导报,2007,4(27):80-81.
[53]杨华,沈雯兰,张媛华,王从亮,何丽娅,丁俊,何朝霞.降糖保肾胶囊治疗糖尿病肾病100例临床研究[J].2007,28(3):10
[54]李红兵,程萧寒,杜茂福.中西医结合治疗中期糖尿病肾病的临床疗效观察[J].四川医学,2010,31(8)：1125-1126.
[55]张月,王凡．六味地黄汤加味治疗糖尿病肾病30例疗效观察[J］．福建中医药,2008,39(5):8－9．
[56]谢立群.活血化瘀法治疗糖尿病肾病80例疗效观察[J］.时珍国医国药,2001,12(8)：721.
[57]柴可夫,柴瑞.糖肾汤对糖尿病大鼠肾脏保护作用的实验研究[J].中医药学刊,2005,23(9):1551-155
[58]彭月芹,孔祥芬,李秋英,等.芪蛭消癥胶囊治疗早期糖尿病肾病90例.河北中医.2008；30(3)：236-237
[59]郭登洲,王月华,张芬芳,等.活血化瘀消症通络中药治疗糖尿病肾病76例临床研究[J].中国全科医学2007,10(20)：1692
[60]刘素荣.程益春教授治疗糖尿病肾病用药特色[J].中国中医药信息杂志,2004,11(11):1017.
[61]郑晓鹏．雷公藤多苷治疗糖尿病肾病的疗效观察[J］．临床和实验医学杂志,2009,8(7):134－135．
[62]李秋英,刘静云,朱红爱,等．中医药治疗糖尿病肾病进展[J］．河北医药,2008,30(6):656－658．
[63]柳刚,关广聚,亓同钢,等.丹参对糖尿病大鼠肾脏的保护作用及其机制研究[J].中西医结合学报,2005,3(6):459-462.
[64]刘红,张伟,李署远.黄芪注射液治疗早期2型糖尿病肾病35例[J].山东中医药大学学报,2001,25(3):202-203.
[65]司廷林,侯慧珍．黄芪注射液对早期糖尿病肾病尿微量清蛋白及内皮素的影响[J］．山东中医药大学学报,2007,31(1):36－37．
[66]施萍,李正.黄芪在糖尿病肾病治疗中降低尿微量白蛋白的作用[J].现代临床医学.2005,31(2):89-90.
[67]王小梅,甄卓丽,陈小芳,袁汉尧,徐军发等.丹参注射液对糖尿病肾病患者血液IL-6、IL-8和TNF-2水平的影响[J].河北医学,2005,11(9):769-772.
[68]吴波,韩萍,刘英敏.金纳多治疗糖尿病早期肾病的临床疗效观察[J］.辽宁中药与临床,2002,5(3)：128-129.
[69]王冬燕,谭智敏．疏血通治疗早期糖尿病肾病40例[J］．山东中医药大学学报,2009,31(4):315－316．
[70]王文,行利,李军昌,等.灯盏花素注射液对糖尿病肾病患者血液流变学的影响[J].第四军医大学学报,2003,24(5):411.
[71]杨益芳.葛根素注射液治疗50例糖尿病肾病的疗效观察[J].泸州医学院学报,2003,26(1):54-55
[72] Wild S, Roglic G, Green A, et al. Global prevalence of diabetes： estimates for the year2000and projections for2030. Diab Care,2004,27(5):1047-1053
[73] Evans JL, Goldfine ID, Maddux BA, et al. Oxidative stress and stress-activatedsignaling pathways: a unifying hypothesis of type2diabetes. Endocr Rev2002,23(5):599-622
[74] Bonnefont-Rousselot D.Glucose and reactive oxygen species.Curr OPin Clin NutrMetab Care,2002,5(5):561-568
[75] Bellomo F,Piccoli C,Cocco T,et al. Regulation by the cAMP cascade of oxygen freeradical balance in mammalian cells. Antioxid Redox Signal,2006,8(3-4):495-502
[76] Trevisi L, Bertoldo A, Agnoletto L, et al. Anti apoptotic and Proliferative Effects of LowConcentrations of7beta hydroxy cholesterol in Human Endothelial Cells via ERKActivation. J Vasc Res,2009,7(3):241-251
[77] Chen HI, Liou SH,Ho SF,et al. Oxidative DNA damage estimated by plasma8-hydroxydeoxyguanosine(8-OHdG): influence of4,4’-methylenebis(2-chloroaniline) exposureand smoking. J Occup Health,2007,49(5):389-398
[78] Chang GM, Kuo MC, Kuo HT, et al. Increased glomerular and extracellularmalondialdehyde levels in patients and rats with diabetic nephropathy. J Lab Clin Med,2005,146(4):210-215
[79] Kowluru RA, Abbas SN, Odenbach S. Reversal of hyperglycaemia and diabeticnephropathy: effect of reinstitution of good metabolic control on oxidative stress in thekidney of diabetic rats. J Diabetes Complications,2004,18:282-288
[80] Xiao H, Li Y, Qi J, et al. Peroxynitrite plays a key role in glomerular lesions in diabeticrats. J Nephrol,2009,22(6):800-808
[81] Ferdinandy P. Peroxynitrite: just an oxidative/nitrosative stressor or a physiologicalregulator as well? Br J Pharmacol,2006,148(1):1-3
[82] Halliwell B. What nitrated tyrosine? Is nitrotyrosine specific as a biomarker ofperoxynitrite formation in vivo? FEBS Lett,1997,411(2-3):157-160
[83] Ischiropoulos H. Biological tyrosine nitration:a pathophysiological function of nitricoxide and reactive oxygen[J]. Arch Biochem Biophys,1998,356:1-11.
[84] Nishikawa T, Edelstein D, Du XL. Normalizing mitochondrial superoxide productionblocks three pathways of hyperglycemia damage[J]. Nature,2000,404(4):787-790.
[85] Shiose A,Kuroda J,Tsuruya K,et al. A novel superoxide producing NAD(p)Hoxidase in kidney.J Biol Chem,2001,276(2):1417-1423
[86] Asaba K,Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabeticnephropathy. Kidney Int,2005,67(5):1890-1898.
[87] Kang SW, Natarajan R, Shahed A,et al. Role of12-lipoxygenase in the stimulation ofP38mitogen-activated protein kinase and collagen in experimental diabetic nephropathyand in glucose stimulated podocytes. J Am Soc Nephrol,2003,14:317-318
[88] Xu Y,Osborne BW,Stanton RC.Diabetes Causes Inhibition of Glucose-6-Phosphatedehydrogenase via Activation of Protein Kinase A which Contributes to Oxidative Stressin Rat Kidney Cortex.Am J Physiol Renal Physiol,2005,289(5):F1040-F1047.
[89]陈玲,贾汝汉,丁国华,等.脱氢抗坏血酸对高糖诱导肾小管上皮细胞产生氧自由基的影响.中华肾脏病杂志,2005,21(10):605-609.
[90] Catherwood MA, Powell LA, Anderson P, et al. Glucose-induced oxidative stress inmesangial cells. Kidney Int,2002,61(2):599-608.
[91] Susztak K, Raft AC, Schiffer M, et al.Glucose-induced reactive oxygen species causeapoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.Diabetes,2006,55(1):225-233
[92] Yard BA, Kahlert S, Engelleiter R, et al. Decreased glomerular expression of agrin indiabetic nephropathy and podocytes, cultured in high glucose medium. ExpNephrol,2001,9(3):214-222.
[93] Mundel P, Shanlkland SJ. Podocyte biology and response to injury. J Am Soc of Nephrol2002,13(12):3005-3015
[94] Jaimes EA, Hua P, Tian RX, et al. Human glomerular endothelium:interplay amongglucose, free fatty acids, angiotensin II,and oxidative stress.Am J Physiol Renal Physiol,2010,298(1): F125-132
[95] Cyrus T, Praticò D, Zhao L, et al.Absence of12/15-lipoxygenase expression decreaseslipid peroxidation and atherogenesis in apolipoprotein efficient mice.Circulation,2001,103(18):2277-2282
[96] Liu YH. Epithelial to mesenchymal transition in renal fibrogenesis: pathologicsignificance, molecular mechanism, and therapeutic intervention. J Am Soc nephrol2004,15(1):1-12
[97] Ha H, Yu MR, Choi YJ, et al. Role of high glucose-induced nuclear factor-kappa Bactivation in monocyte chemoattractant protein-1expression by mesangial cells[J]. JAmSoc Nephrol,2002,13(4):894-902.
[98] Lee EA, Seo JY, Jiang Z, et al. Reaction oxygen species mediate high glucose inducedplasminogen activator inhibitor-1up-regulation in mesangial cells and in diabetic kidney.Kidney international,2005,67(5):1762-1771
[99] Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-beta1-inducedmitogen-activated protein kinase activation and epithelial mesenchymal transition inrenal tubular epithelial cells, J Am Soc Nephrol,2005,16(3):667-675
[100] Arita Y, Kibara S, Ouchi N,et al. Paradoxical decrease of an adipose-specific protein,adiponectin, in obesity, Biochem Biophys Res Commun1999,257(1):79-83.
[101] Fruebis J,Tsao TS,Javorschi S,et al. Proteolytic cleavage Product of30-kDa adipocytecomplement-related protein increases fatty acid oxidation in muscle and causes weightloss in mice[J].Proc Natl Acad Sci USA,2001,98(4):2005-2010.
[102] Yamauchi T, Kamon J,Waki H,et al. The fa-derived hormone adiponectin Reversesinsulin resistance associated with both lipoatrophy and obesity[J].Nat Med,2001,7(8):941-946.
[103] Yamauchi T, Kamon J, Ito Y.et al. Cloning of adiponectin receptors that mediateantidiabetic metabolic effects[J]．Nature,2003,423:762-769.
[104] Staiger H, Kaltenbach S, Staiger K, et al. Expression of adiponectin receptor mRNA inhuman skeletal muscle cells is related to in vivo parameters of glucose and lipidmetabolism[J]. Diabetes,2004,53(9):2195-2201.
[105] Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in micelacking adiponectin/ACRP30. Nat Med,2002,8(7):731-737.
[106] Nawrocki AR, Rajala MW, Tomas E et al. Mice lacking adiponectin show decreasedhepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem,2006,281(5):2654-2660.
[107] Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulinresistance and neointimal formation. J Biol Chem.2002,277(29):25863-25866.
[108] Berg AH, Combs TP, Du X, et al. The adipocyte secreted protein Acrp30enhanceshepatic insulin action. Nat Med,2001,7(8):947-953.
[109] Satoh H, Nguyen MT, Trujillo M, et al. Adenovirus-mediated adiponectin expressionaugments skeletal muscle insulin sensitivity in male Wistar rats. Diabetes,2005,54(5):1304-1313.
[110] Combs TP, Pajvani UB, Berg AH, et al. A transgenic mouse with a deletion in thecollagenous domain of adiponectin displays elevated circulating adiponectin andimproved insulin sensitivity. Endocrinology,2004,145(1):367-383.
[111] Hotta K,Funahashi T,Arita Y,et al. Plasma concentrations of a novel,adipose-specificprotein,adiponectin,in Type2diabetic Patients [J]. Arterioscler Thromb Vasc Biol,2000,20(6):1595-1599
[112] Hotta K, Funahashi T, Bodkin NL,et al. Circulation concentrations of the adipocyteprotein,adiponectin,are decreased in Parallel with reduced insulin sensitivity during theprogression to type2diabetes in thesis monkeys.Diabetes,2001,50(5):1126-1133
[113] Daimon M,Oizumi T,Saitoh T,et al.Decreased serum levels of adiponectin are a riskfactor for the progression to type2diabetes in the Japanese population:the Funagatastudy.Diabetes Care,2003,26(7):2015-2020
[114] Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type2diabetes in the Pima Indian population. Lancet,2002,360(9326):57-58.
[115] Choi KM, Lee J, Lee KW, et al. Serum adiponectin concentrations predict thedevelopments of type2diabetes and the metabolic syndrome in elderly Koreans.ClinEndocrinol Metab,2004,61(1):75-80.
[116] Yamamoto Y, Hirose H, Saito I, et al. Adiponectin, an adipocyte-derived protein,predicts future insulin resistance: two-year follow-up study in Japanesepopulation. J Clin Endocrinol Metab,2004,89(1):87-90.
[117] Stumvoll M,Tschritter O,Fritsehe A,et al. Associationof the T-G Polymorphism inadiponectin (Exon2)with obesity and insulin sensitivity:interaction with family historyof diabetes[J].D iabetes,2002,51:37-41.
[118] Holst JJ,Binderup M.Fatty tissue and insulin resistance:resistin and adiponectin [J].Ugeskr Laeger,2002,164(16):2173.
[119] Jun Koshimura,Hiroki Fujita,Takuma Narita,et al.Urinary adiponectin excretion isincreased in patients with overt diabetic nephropathy. Biochem and Biophys ResCommun,2004,316:165-169.
[120] Helen C,Jonathan Krakoff,Tohru Funahashi,et al.Adiponectin concentrations areinfluenced by renal function and diabetes duration in pima Indian with Type2diabetes.J Clin Endocrinol Metab,2004,89(8):4010-4017
[121]杨一芬,卿之驹,黄干.2型糖尿病肾病患者血清瘦素和脂联素检测的研究[J].实用预防医学.2007,14(5)：1415-1417。
[122]龚琴,周成林.2型糖尿病肾病患者血清IL-18、脂联素、胱抑素C水平及其临床意义的研究[J].中国民族民间医药.2009,(24)：56-60.
[123] Yenicesu M,Yilmaz MI,Caglar K, et al. Adiponectin level is reduced and inverselycorrelated with the degree of proteinuria in type2diabetic patients.Clin Nephrol,2005,64(1):12-19.
[124] Maeda K,Okubo K,Shimomura I,et al.cDNA cloning and expression of a novel adiposespecific collagen-like factor,apMl (adipose most abundant gene Transcript l).BiochemBiophys Res Commun,1996,221:286-289.
[125] Saito T,Saito O,Kawano T,et al.Elevation of serum adiponectin and CD146levels indiabetic nephropathy.Diabetes Res Clin,2007Oct;78(l):85-92.
[126]蔡珂丹,闫蕾,孙子林等.2型糖尿病肾病患者血清脂联素水平的变化[J].肾脏病与透析肾移植杂志.2009,18(1)：39-43.
[127] Yilmaz MI,Saqlam M,Qureshi AR,et al.Endothelial dysfunction in type-2diabeticswith early diabetic nephropathy is associated with low circulating adiponectin.Nephro1Dial Transplant,2008Jan10.
[128] Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice fromdiabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem,2003,278(4):2461-2468.
[129] Furukawa K,HoriM,Ouehi N,et al. Adiponectin down-regulates acyl coenzyme A:cholesterol acyltransferase-1in cultured human monocyte-derived macrophages.Bioehem BioPhys Res Commun,2004,317:831-836
[130] Nakanishi S,Yamane K,Kamei N,et al.A protective effect of adiponectin againstoxidative stress in Japanese Americans:the association between adiponectin or leptinand urinary is oprostane [J].Metabolism,2005,54:194-199.
[131]唐镇生主编.分子外科与基因治疗[M].上海医科大学出版社1999年7月:7-8
[132] Yoshida D,Watanabe K, Noha M,et al. Anti-invasive effect of an anti-matrixmetalloproteinase agent in a murine brain slice model using the serial monitoring ofgreen fluorescent protein-labeled gliomaeells.J Neurosurgery,2003,52(l):187-197
[133] Ouchi N, Kobayashi H, Kihara S, et al. Adiponectin stimulates angiogenesis bypromoting cross-talk between AMP-activated protein kinase and Akt signaling inendothelial cells. J Biol Chem,2004,279(2):1304-1309.
[134] Chen H, Montagnani M, Funahashi T, et al. Adiponectin stimulates production ofnitric oxide in vascular endothelial cells. J Biol Chem,2003,278(45):45021-45026.
[135] Motoshima H,WuX,Mahedev K, et al. Adiponectin suppresses proliferation ansuperoxide generation and enhances eNOS activity in endothelial cells treated withoxidized LDL. Biochem Biophys Res Commun,2004,315:264-271.
[136]袁芳,等.脂联素对糖尿病大鼠的肾脏保护作用及其抗氧化机制探讨[J].南方医科大学学报,2010：30(3)
[137]郭啸华,刘志红,李恒,黎磊石.高糖高脂饮食诱导的2型糖尿病大鼠模型及其肾病特点.中国糖尿病杂志,2002,1(5):290~294
[138]殴阳涓,姜傥.肾脏的损伤性诊断[J].中华检验医学杂志.2005,28(8)：877-879
[139] Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: arolefor the glomerular endothelium? Diabetologia,2008, I (5):714-725
[140] Tschritter O, Fritsche A,Thamer C, et al. Plasma adiponectin concentrationspredictinsulin sensitity of both glucose and lipid metabolism.Diabetes,2003,52(2):239-243.
[141] Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type2diabetes:close association with insulin resistance and hyperinsulinemia. J ClinEndocrinol Metab,2001,86(5):1930-1935.
[142] Holst JJ,Binderup M. Fatty tissue and insulin resistance:resistin and adiponectin.Ugeskr L aeger,2002,164(16):2173.
[143] Berg AH,Combs TP,Du X et al.The adipocyte-secreted protein Acrp30enhanceshepatic insulin action.Nat Med2001,7(8):947-953
[144] Civitarese AE, Jenkinson CP, Richardson D, et al. Adiponectin receptors geneexpression and insulin sensitivity in non-diabetic Mexican American with or without afamily history of Type2diabetes[J]. Diabetologia.2004;47(5):816-820.
[145] Singh DK, Winocour P,Farrington K.Oxidative stress in early diabeticnephropathy:fueling the fire. Nat Rev Endocrinol,2011,7(3):176~184
[146] Jiang T,?Huang Z,Lin Y,et al.The protective role of Nrf2instreptozotocin-induceddiabetic nephropathy.Diabetes,2010,59(4):850~860
[147] Brownlee M. Biochemistry and molecular cell biology of diabetic complications.Nature,2001,414(6865):813-820
[148] Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulinresistance, diabetes, and cardiovascular disease? The common soilhypothesis revisited. Arterioscler Thromb Vasc Bio1,2004,24(5):816-823
[149] Azzi A, Davies K J, Kelly F.Free RadicalBiology-Term inology andCritical Thinking.FEBS Lett,2004,558(1-3):3-6
[150] Van Dam PS. Oxidative Stress and diabetic neuropathy: pathophysiologicalmechanisms and treatment perspectives. DiabetesMetab Res Re,2002,18(3):176-184
[151] Nishikawa T,Edelstein D,Du XL,et al.Normalizing mitochondrialsuperoxideproduction blocks three pathways of hyperglycaemic damage.Nature.2000,404(6779):787-790
[152] Xiao H,Li Y,Qi J,et al.Peroxynitrite plays a key role in glomerularlesions in diabeticrats. J Nephrol,2009,22(6):800-808
[153] National Kidney Foundation.Kidney Disease Outcome QualityInitiative. K/DOQIclinical practice guidelines for chronic kid-ney disease: evaluation, classification, andstratification. Am J Kidney Dis,2002,39(2Suppl2):S1-S246.
[154] Dalla VM, Saller A, Bortoloso E, et al. Structural in-volvement in type1and type2diabetic nephropathy[J]. Diabetes Metab,2000,26(Suppl4):8-14
[155] Song JS, Huh KH, Park J, et al.Effects of Inosine Monophosphate DehydrogenaseInhibition on High Glucose-Induced Cellular Reactive Oxygen Species in MesangialCells.Transplant Proc,2008,40(2):464-466
[156] Yeh CH,Chang CK,Cheng MF,et al.The antioxidative effect of bonemorphogeneticprotein-7against high glucose-induced oxidative stress in mesangial cells.BiochemBiophys Res Commun,2009,382(2):292-297
[157] Marrero MB, Banes-Berceli AK, Stern DM, et al. Role of the JAK/STATsignalingpathway in diabetic nephropathy. Am J Physiol Renal Physiol,2006,290(4): F762~F768
[158] Rhyu DY,Yang Y,Ha H,et al.Role of reactive oxygen species in TGF-beta1-inducedmitogen-activated protein kinase activation and epithelialmesenchymal transition inrenal tubular epithelial cells.J Am Soc Nephrol,2005,16(3):667-675
[159] Nakajima T, Hasegawa G, Kamiuchi K, et al. Differ-ential regulation of intracellularredox state by extra-cellular matrix proteins in glomerular mesangial cells:Potentialrole in diabetic nephropathy[J]. Redox Rep,2006,11(5):223-230.
[160]薛华,孙喜明.蛋白激酶C与糖尿病肾病的关系[J].临床和实验医学杂志,2006,5(4):417.
[2]林兰.治疗糖尿病肾病的经验[J].辽宁中医杂志,2000,27(4):145
[3]南征.消渴肾病(糖尿病肾病)研究[M].第一版.长春.吉林科学技术出版社,2001,5:1-5.
[4]任继学.任继学经验集.第一版.北京.人民卫生出版社出版,2000,195-197.
[5]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[J].中国中西医结合肾病,2005,6(5):253-254
[6]封翠云.糖尿病肾病的中医病名探讨[J].国医论坛,2007,22(2):22
[7]林兰.中西医结合糖尿病学[M］.北京：中国医药科技出版社,1999：395-407.
[8]张先闻.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.
[9]郭向东,王小琴,熊玮．中西医结合治疗早期糖尿病肾病33例观察[J］．实用中医药杂志,2008,1,1(24):24－25．
[10]贺学林.陈以平教授治疗临床经验[J].中国中西医结合肾病杂志,2000,1(1):7-8.
[11]吴以岭,魏聪,贾振华．从络病学说探讨糖尿病肾病的病机[J］．中国中医基础医学杂志,2007,13(9):590－591
[12]赵会贤,苏荣华.DN的病因病机及证治浅识[J].中医药学刊.2004,9:1760-1761.
[13]李琪,高阳,刘启庭.糖肾康治疗2型DN的临床研究[J].辽宁中医杂志,1998,(3):114-116.
[14]吕仁和,赵进喜,王世东.糖尿病及其并发症的临床研究.新中医,2001,33(3):4
[15]张岩．糖尿病肾病的中医病因病机浅析[J］．光明中医,2010(3):406－407.
[16]陈筱云,赵丽娟.从瘀论治糖尿病肾病[J].中国中医基础医学杂志,2002,8(7):53-54
[17]方水林．糖尿病肾病从瘀论治探讨[J］．实用中医内科杂志,2006,20(6):606－607．
[18]李小会,董正华.糖尿病肾病病因病机探讨[J].陕西中医,2005,26(6):552-553
[19]宋述菊,牟宗秀.糖尿病肾病病因病机及辨治探讨.山东中医杂志,1999,18(4):147-148
[20]邱晓堂．张永杰教授从脾论治糖尿病肾病[J］．河南中医,2005,25(1):26－27
[21]范晔,莫传伟,陈群,等．糖尿病肾病五脏相关研究[J］．安徽中医学院学报,2008,27(1):17－18．
[22]张彤.叶景华治疗糖尿病肾病经验[J］.中医杂志,2003(10)：734-735.
[23]王秀珍.健脾固肾汤治疗早期糖尿病肾病40例[J].浙江中医杂志,2004,(6):332
[24]杨文军,赵孔华.脾肾气机升降失常与糖尿病肾病关系探讨[J］.山东中医药大学学报,2005,29(3)：188-189.
[25]李俊美.吕仁和教授治疗糖尿病肾病的经验[J］.四川中医,2009,27(5)：1-3.
[26]丁英钧,肖永华,傅强,潘莉,赵进喜.糖尿病肾病“微型癥瘕”病理假说解析[J].中华中医药杂志,2009,24(1)：27-28
[27]南征.毒损肾络所致消渴肾病机理浅说[J].吉林中医药,2007,27(2):11
[28]于敏,张波,史耀勋,南征.南征教授“毒损肾络”理论学说探析及临床运用[J].中华中医药学刊,2010,28(2)：244-245
[29]曹和欣,何立群.糖肾宁对早期糖尿病肾病大鼠高滤过的影响[J］.上海中医药杂志,2001,35(5)：19-21.
[30]周晖.高彦彬教授诊治糖尿病肾病的临床经验[J］.辽宁中医杂志,2009,36(7)：1078-1079.
[31]魏军平,林兰·中西医结合治疗糖尿病研究进展[J]·医学研究杂志,2007,36(4):16-19.
[32]吕仁和,赵进喜,王世东.糖尿病及其并发症的临床研究[J].新中医,2001,33(3)：4
[33]詹锐文.糖尿病肾病析义[J].辽宁中医杂志,2004,31(7):566-567.
[34]王耀献,王翚.糖尿病肾病的中医分型辨证论治[J］.糖尿病新世界,2005,8(4)：22.
[35]肖永华.吕仁和治疗糖尿病肾病经验[J].世界中医药,2007,2(3)：151-153.
[36]魏军平,林兰.糖尿病肾病的辨治经验[J].国际中医中药杂志,2007,29(3):177-178.
[37]韩云平．李小娟教授治疗糖尿病肾病经验撷要[J］．实用中医内科杂志,2009,23(1):13－14．
[38]徐延.中西医结合治疗糖尿病肾病33例[J］.四川中医,2002,20(6)：38-39.
[39]李朝晖.中西医结合治疗糖尿病肾病临床观察[J].河北中医,2005,27(2)：122－123.
[40]王小光,王亚丽,张佩清.张琪教授辨治糖尿病肾病经验介绍[J］.新中医,2005,37(3)：20-21.
[41]叶任高.中西医结合肾脏病学[M].北京:人民卫生出版社,2003:305-307.
[42]吕贵德.辨证论治糖尿病肾病38例疗效观察[J].河北中医,2002,24(2):103-104.
[43]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)：42-43.
[44]赵东鹰.辨证论治结合西药治疗糖尿病肾病56例[J].陕西中医,2007,28(4):415-416
[45]吴以岭,魏聪,贾振华,朱昭明.从络病病学说论治糖尿病肾病[J].疑难病杂志,2007,6(6):350-351.
[46]李桂芝,郑万发.中医辨证治疗糖尿病肾病100例疗效观察.云南中医中药杂志,2007,28(1):17
[47]林兰,倪青,高齐健,等.糖微康胶囊治疗糖尿病肾病的临床观察[J].中国中西医结合杂志,2000,20(11):811-814
[48]高彦彬,赵慧玲,关崧等.糖肾宁治疗气阴两虚、络脉瘀滞型早期糖尿病肾病临床研究[J].中华中医药杂志,2006,21(7):409-411
[49]董正华,曹广顺,曹雯,等.通络益肾汤治疗糖尿病肾病30例[J].上海中医药杂志,2007,41(9),46-48.
[50]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.
[51]李亚文,杨焱,陈凤娇,陈化龙.血府逐瘀汤加减治疗糖尿病肾病40例临床观察[J].中国现代药物应用,2009,3(3):95-96
[52]刘建平.参芪益肾汤治疗早期糖尿病肾病35例疗效观察[J].中国医药导报,2007,4(27):80-81.
[53]杨华,沈雯兰,张媛华,王从亮,何丽娅,丁俊,何朝霞.降糖保肾胶囊治疗糖尿病肾病100例临床研究[J].2007,28(3):10
[54]李红兵,程萧寒,杜茂福.中西医结合治疗中期糖尿病肾病的临床疗效观察[J].四川医学,2010,31(8)：1125-1126.
[55]张月,王凡．六味地黄汤加味治疗糖尿病肾病30例疗效观察[J］．福建中医药,2008,39(5):8－9．
[56]谢立群.活血化瘀法治疗糖尿病肾病80例疗效观察[J］.时珍国医国药,2001,12(8)：721.
[57]柴可夫,柴瑞.糖肾汤对糖尿病大鼠肾脏保护作用的实验研究[J].中医药学刊,2005,23(9):1551-155
[58]彭月芹,孔祥芬,李秋英,等.芪蛭消癥胶囊治疗早期糖尿病肾病90例.河北中医.2008；30(3)：236-237
[59]郭登洲,王月华,张芬芳,等.活血化瘀消症通络中药治疗糖尿病肾病76例临床研究[J].中国全科医学2007,10(20)：1692
[60]刘素荣.程益春教授治疗糖尿病肾病用药特色[J].中国中医药信息杂志,2004,11(11):1017.
[61]郑晓鹏．雷公藤多苷治疗糖尿病肾病的疗效观察[J］．临床和实验医学杂志,2009,8(7):134－135．
[62]李秋英,刘静云,朱红爱,等．中医药治疗糖尿病肾病进展[J］．河北医药,2008,30(6):656－658．
[63]柳刚,关广聚,亓同钢,等.丹参对糖尿病大鼠肾脏的保护作用及其机制研究[J].中西医结合学报,2005,3(6):459-462.
[64]刘红,张伟,李署远.黄芪注射液治疗早期2型糖尿病肾病35例[J].山东中医药大学学报,2001,25(3):202-203.
[65]司廷林,侯慧珍．黄芪注射液对早期糖尿病肾病尿微量清蛋白及内皮素的影响[J］．山东中医药大学学报,2007,31(1):36－37．
[66]施萍,李正.黄芪在糖尿病肾病治疗中降低尿微量白蛋白的作用[J].现代临床医学.2005,31(2):89-90.
[67]王小梅,甄卓丽,陈小芳,袁汉尧,徐军发等.丹参注射液对糖尿病肾病患者血液IL-6、IL-8和TNF-2水平的影响[J].河北医学,2005,11(9):769-772.
[68]吴波,韩萍,刘英敏.金纳多治疗糖尿病早期肾病的临床疗效观察[J］.辽宁中药与临床,2002,5(3)：128-129.
[69]王冬燕,谭智敏．疏血通治疗早期糖尿病肾病40例[J］．山东中医药大学学报,2009,31(4):315－316．
[70]王文,行利,李军昌,等.灯盏花素注射液对糖尿病肾病患者血液流变学的影响[J].第四军医大学学报,2003,24(5):411.
[71]杨益芳.葛根素注射液治疗50例糖尿病肾病的疗效观察[J].泸州医学院学报,2003,26(1):54-55
[72] Wild S, Roglic G, Green A, et al. Global prevalence of diabetes： estimates for the year2000and projections for2030. Diab Care,2004,27(5):1047-1053
[73] Evans JL, Goldfine ID, Maddux BA, et al. Oxidative stress and stress-activatedsignaling pathways: a unifying hypothesis of type2diabetes. Endocr Rev2002,23(5):599-622
[74] Bonnefont-Rousselot D.Glucose and reactive oxygen species.Curr OPin Clin NutrMetab Care,2002,5(5):561-568
[75] Bellomo F,Piccoli C,Cocco T,et al. Regulation by the cAMP cascade of oxygen freeradical balance in mammalian cells. Antioxid Redox Signal,2006,8(3-4):495-502
[76] Trevisi L, Bertoldo A, Agnoletto L, et al. Anti apoptotic and Proliferative Effects of LowConcentrations of7beta hydroxy cholesterol in Human Endothelial Cells via ERKActivation. J Vasc Res,2009,7(3):241-251
[77] Chen HI, Liou SH,Ho SF,et al. Oxidative DNA damage estimated by plasma8-hydroxydeoxyguanosine(8-OHdG): influence of4,4’-methylenebis(2-chloroaniline) exposureand smoking. J Occup Health,2007,49(5):389-398
[78] Chang GM, Kuo MC, Kuo HT, et al. Increased glomerular and extracellularmalondialdehyde levels in patients and rats with diabetic nephropathy. J Lab Clin Med,2005,146(4):210-215
[79] Kowluru RA, Abbas SN, Odenbach S. Reversal of hyperglycaemia and diabeticnephropathy: effect of reinstitution of good metabolic control on oxidative stress in thekidney of diabetic rats. J Diabetes Complications,2004,18:282-288
[80] Xiao H, Li Y, Qi J, et al. Peroxynitrite plays a key role in glomerular lesions in diabeticrats. J Nephrol,2009,22(6):800-808
[81] Ferdinandy P. Peroxynitrite: just an oxidative/nitrosative stressor or a physiologicalregulator as well? Br J Pharmacol,2006,148(1):1-3
[82] Halliwell B. What nitrated tyrosine? Is nitrotyrosine specific as a biomarker ofperoxynitrite formation in vivo? FEBS Lett,1997,411(2-3):157-160
[83] Ischiropoulos H. Biological tyrosine nitration:a pathophysiological function of nitricoxide and reactive oxygen[J]. Arch Biochem Biophys,1998,356:1-11.
[84] Nishikawa T, Edelstein D, Du XL. Normalizing mitochondrial superoxide productionblocks three pathways of hyperglycemia damage[J]. Nature,2000,404(4):787-790.
[85] Shiose A,Kuroda J,Tsuruya K,et al. A novel superoxide producing NAD(p)Hoxidase in kidney.J Biol Chem,2001,276(2):1417-1423
[86] Asaba K,Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabeticnephropathy. Kidney Int,2005,67(5):1890-1898.
[87] Kang SW, Natarajan R, Shahed A,et al. Role of12-lipoxygenase in the stimulation ofP38mitogen-activated protein kinase and collagen in experimental diabetic nephropathyand in glucose stimulated podocytes. J Am Soc Nephrol,2003,14:317-318
[88] Xu Y,Osborne BW,Stanton RC.Diabetes Causes Inhibition of Glucose-6-Phosphatedehydrogenase via Activation of Protein Kinase A which Contributes to Oxidative Stressin Rat Kidney Cortex.Am J Physiol Renal Physiol,2005,289(5):F1040-F1047.
[89]陈玲,贾汝汉,丁国华,等.脱氢抗坏血酸对高糖诱导肾小管上皮细胞产生氧自由基的影响.中华肾脏病杂志,2005,21(10):605-609.
[90] Catherwood MA, Powell LA, Anderson P, et al. Glucose-induced oxidative stress inmesangial cells. Kidney Int,2002,61(2):599-608.
[91] Susztak K, Raft AC, Schiffer M, et al.Glucose-induced reactive oxygen species causeapoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.Diabetes,2006,55(1):225-233
[92] Yard BA, Kahlert S, Engelleiter R, et al. Decreased glomerular expression of agrin indiabetic nephropathy and podocytes, cultured in high glucose medium. ExpNephrol,2001,9(3):214-222.
[93] Mundel P, Shanlkland SJ. Podocyte biology and response to injury. J Am Soc of Nephrol2002,13(12):3005-3015
[94] Jaimes EA, Hua P, Tian RX, et al. Human glomerular endothelium:interplay amongglucose, free fatty acids, angiotensin II,and oxidative stress.Am J Physiol Renal Physiol,2010,298(1): F125-132
[95] Cyrus T, Praticò D, Zhao L, et al.Absence of12/15-lipoxygenase expression decreaseslipid peroxidation and atherogenesis in apolipoprotein efficient mice.Circulation,2001,103(18):2277-2282
[96] Liu YH. Epithelial to mesenchymal transition in renal fibrogenesis: pathologicsignificance, molecular mechanism, and therapeutic intervention. J Am Soc nephrol2004,15(1):1-12
[97] Ha H, Yu MR, Choi YJ, et al. Role of high glucose-induced nuclear factor-kappa Bactivation in monocyte chemoattractant protein-1expression by mesangial cells[J]. JAmSoc Nephrol,2002,13(4):894-902.
[98] Lee EA, Seo JY, Jiang Z, et al. Reaction oxygen species mediate high glucose inducedplasminogen activator inhibitor-1up-regulation in mesangial cells and in diabetic kidney.Kidney international,2005,67(5):1762-1771
[99] Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-beta1-inducedmitogen-activated protein kinase activation and epithelial mesenchymal transition inrenal tubular epithelial cells, J Am Soc Nephrol,2005,16(3):667-675
[100] Arita Y, Kibara S, Ouchi N,et al. Paradoxical decrease of an adipose-specific protein,adiponectin, in obesity, Biochem Biophys Res Commun1999,257(1):79-83.
[101] Fruebis J,Tsao TS,Javorschi S,et al. Proteolytic cleavage Product of30-kDa adipocytecomplement-related protein increases fatty acid oxidation in muscle and causes weightloss in mice[J].Proc Natl Acad Sci USA,2001,98(4):2005-2010.
[102] Yamauchi T, Kamon J,Waki H,et al. The fa-derived hormone adiponectin Reversesinsulin resistance associated with both lipoatrophy and obesity[J].Nat Med,2001,7(8):941-946.
[103] Yamauchi T, Kamon J, Ito Y.et al. Cloning of adiponectin receptors that mediateantidiabetic metabolic effects[J]．Nature,2003,423:762-769.
[104] Staiger H, Kaltenbach S, Staiger K, et al. Expression of adiponectin receptor mRNA inhuman skeletal muscle cells is related to in vivo parameters of glucose and lipidmetabolism[J]. Diabetes,2004,53(9):2195-2201.
[105] Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in micelacking adiponectin/ACRP30. Nat Med,2002,8(7):731-737.
[106] Nawrocki AR, Rajala MW, Tomas E et al. Mice lacking adiponectin show decreasedhepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem,2006,281(5):2654-2660.
[107] Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulinresistance and neointimal formation. J Biol Chem.2002,277(29):25863-25866.
[108] Berg AH, Combs TP, Du X, et al. The adipocyte secreted protein Acrp30enhanceshepatic insulin action. Nat Med,2001,7(8):947-953.
[109] Satoh H, Nguyen MT, Trujillo M, et al. Adenovirus-mediated adiponectin expressionaugments skeletal muscle insulin sensitivity in male Wistar rats. Diabetes,2005,54(5):1304-1313.
[110] Combs TP, Pajvani UB, Berg AH, et al. A transgenic mouse with a deletion in thecollagenous domain of adiponectin displays elevated circulating adiponectin andimproved insulin sensitivity. Endocrinology,2004,145(1):367-383.
[111] Hotta K,Funahashi T,Arita Y,et al. Plasma concentrations of a novel,adipose-specificprotein,adiponectin,in Type2diabetic Patients [J]. Arterioscler Thromb Vasc Biol,2000,20(6):1595-1599
[112] Hotta K, Funahashi T, Bodkin NL,et al. Circulation concentrations of the adipocyteprotein,adiponectin,are decreased in Parallel with reduced insulin sensitivity during theprogression to type2diabetes in thesis monkeys.Diabetes,2001,50(5):1126-1133
[113] Daimon M,Oizumi T,Saitoh T,et al.Decreased serum levels of adiponectin are a riskfactor for the progression to type2diabetes in the Japanese population:the Funagatastudy.Diabetes Care,2003,26(7):2015-2020
[114] Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type2diabetes in the Pima Indian population. Lancet,2002,360(9326):57-58.
[115] Choi KM, Lee J, Lee KW, et al. Serum adiponectin concentrations predict thedevelopments of type2diabetes and the metabolic syndrome in elderly Koreans.ClinEndocrinol Metab,2004,61(1):75-80.
[116] Yamamoto Y, Hirose H, Saito I, et al. Adiponectin, an adipocyte-derived protein,predicts future insulin resistance: two-year follow-up study in Japanesepopulation. J Clin Endocrinol Metab,2004,89(1):87-90.
[117] Stumvoll M,Tschritter O,Fritsehe A,et al. Associationof the T-G Polymorphism inadiponectin (Exon2)with obesity and insulin sensitivity:interaction with family historyof diabetes[J].D iabetes,2002,51:37-41.
[118] Holst JJ,Binderup M.Fatty tissue and insulin resistance:resistin and adiponectin [J].Ugeskr Laeger,2002,164(16):2173.
[119] Jun Koshimura,Hiroki Fujita,Takuma Narita,et al.Urinary adiponectin excretion isincreased in patients with overt diabetic nephropathy. Biochem and Biophys ResCommun,2004,316:165-169.
[120] Helen C,Jonathan Krakoff,Tohru Funahashi,et al.Adiponectin concentrations areinfluenced by renal function and diabetes duration in pima Indian with Type2diabetes.J Clin Endocrinol Metab,2004,89(8):4010-4017
[121]杨一芬,卿之驹,黄干.2型糖尿病肾病患者血清瘦素和脂联素检测的研究[J].实用预防医学.2007,14(5)：1415-1417。
[122]龚琴,周成林.2型糖尿病肾病患者血清IL-18、脂联素、胱抑素C水平及其临床意义的研究[J].中国民族民间医药.2009,(24)：56-60.
[123] Yenicesu M,Yilmaz MI,Caglar K, et al. Adiponectin level is reduced and inverselycorrelated with the degree of proteinuria in type2diabetic patients.Clin Nephrol,2005,64(1):12-19.
[124] Maeda K,Okubo K,Shimomura I,et al.cDNA cloning and expression of a novel adiposespecific collagen-like factor,apMl (adipose most abundant gene Transcript l).BiochemBiophys Res Commun,1996,221:286-289.
[125] Saito T,Saito O,Kawano T,et al.Elevation of serum adiponectin and CD146levels indiabetic nephropathy.Diabetes Res Clin,2007Oct;78(l):85-92.
[126]蔡珂丹,闫蕾,孙子林等.2型糖尿病肾病患者血清脂联素水平的变化[J].肾脏病与透析肾移植杂志.2009,18(1)：39-43.
[127] Yilmaz MI,Saqlam M,Qureshi AR,et al.Endothelial dysfunction in type-2diabeticswith early diabetic nephropathy is associated with low circulating adiponectin.Nephro1Dial Transplant,2008Jan10.
[128] Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice fromdiabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem,2003,278(4):2461-2468.
[129] Furukawa K,HoriM,Ouehi N,et al. Adiponectin down-regulates acyl coenzyme A:cholesterol acyltransferase-1in cultured human monocyte-derived macrophages.Bioehem BioPhys Res Commun,2004,317:831-836
[130] Nakanishi S,Yamane K,Kamei N,et al.A protective effect of adiponectin againstoxidative stress in Japanese Americans:the association between adiponectin or leptinand urinary is oprostane [J].Metabolism,2005,54:194-199.
[131]唐镇生主编.分子外科与基因治疗[M].上海医科大学出版社1999年7月:7-8
[132] Yoshida D,Watanabe K, Noha M,et al. Anti-invasive effect of an anti-matrixmetalloproteinase agent in a murine brain slice model using the serial monitoring ofgreen fluorescent protein-labeled gliomaeells.J Neurosurgery,2003,52(l):187-197
[133] Ouchi N, Kobayashi H, Kihara S, et al. Adiponectin stimulates angiogenesis bypromoting cross-talk between AMP-activated protein kinase and Akt signaling inendothelial cells. J Biol Chem,2004,279(2):1304-1309.
[134] Chen H, Montagnani M, Funahashi T, et al. Adiponectin stimulates production ofnitric oxide in vascular endothelial cells. J Biol Chem,2003,278(45):45021-45026.
[135] Motoshima H,WuX,Mahedev K, et al. Adiponectin suppresses proliferation ansuperoxide generation and enhances eNOS activity in endothelial cells treated withoxidized LDL. Biochem Biophys Res Commun,2004,315:264-271.
[136]袁芳,等.脂联素对糖尿病大鼠的肾脏保护作用及其抗氧化机制探讨[J].南方医科大学学报,2010：30(3)
[137]郭啸华,刘志红,李恒,黎磊石.高糖高脂饮食诱导的2型糖尿病大鼠模型及其肾病特点.中国糖尿病杂志,2002,1(5):290~294
[138]殴阳涓,姜傥.肾脏的损伤性诊断[J].中华检验医学杂志.2005,28(8)：877-879
[139] Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: arolefor the glomerular endothelium? Diabetologia,2008, I (5):714-725
[140] Tschritter O, Fritsche A,Thamer C, et al. Plasma adiponectin concentrationspredictinsulin sensitity of both glucose and lipid metabolism.Diabetes,2003,52(2):239-243.
[141] Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type2diabetes:close association with insulin resistance and hyperinsulinemia. J ClinEndocrinol Metab,2001,86(5):1930-1935.
[142] Holst JJ,Binderup M. Fatty tissue and insulin resistance:resistin and adiponectin.Ugeskr L aeger,2002,164(16):2173.
[143] Berg AH,Combs TP,Du X et al.The adipocyte-secreted protein Acrp30enhanceshepatic insulin action.Nat Med2001,7(8):947-953
[144] Civitarese AE, Jenkinson CP, Richardson D, et al. Adiponectin receptors geneexpression and insulin sensitivity in non-diabetic Mexican American with or without afamily history of Type2diabetes[J]. Diabetologia.2004;47(5):816-820.
[145] Singh DK, Winocour P,Farrington K.Oxidative stress in early diabeticnephropathy:fueling the fire. Nat Rev Endocrinol,2011,7(3):176~184
[146] Jiang T,?Huang Z,Lin Y,et al.The protective role of Nrf2instreptozotocin-induceddiabetic nephropathy.Diabetes,2010,59(4):850~860
[147] Brownlee M. Biochemistry and molecular cell biology of diabetic complications.Nature,2001,414(6865):813-820
[148] Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulinresistance, diabetes, and cardiovascular disease? The common soilhypothesis revisited. Arterioscler Thromb Vasc Bio1,2004,24(5):816-823
[149] Azzi A, Davies K J, Kelly F.Free RadicalBiology-Term inology andCritical Thinking.FEBS Lett,2004,558(1-3):3-6
[150] Van Dam PS. Oxidative Stress and diabetic neuropathy: pathophysiologicalmechanisms and treatment perspectives. DiabetesMetab Res Re,2002,18(3):176-184
[151] Nishikawa T,Edelstein D,Du XL,et al.Normalizing mitochondrialsuperoxideproduction blocks three pathways of hyperglycaemic damage.Nature.2000,404(6779):787-790
[152] Xiao H,Li Y,Qi J,et al.Peroxynitrite plays a key role in glomerularlesions in diabeticrats. J Nephrol,2009,22(6):800-808
[153] National Kidney Foundation.Kidney Disease Outcome QualityInitiative. K/DOQIclinical practice guidelines for chronic kid-ney disease: evaluation, classification, andstratification. Am J Kidney Dis,2002,39(2Suppl2):S1-S246.
[154] Dalla VM, Saller A, Bortoloso E, et al. Structural in-volvement in type1and type2diabetic nephropathy[J]. Diabetes Metab,2000,26(Suppl4):8-14
[155] Song JS, Huh KH, Park J, et al.Effects of Inosine Monophosphate DehydrogenaseInhibition on High Glucose-Induced Cellular Reactive Oxygen Species in MesangialCells.Transplant Proc,2008,40(2):464-466
[156] Yeh CH,Chang CK,Cheng MF,et al.The antioxidative effect of bonemorphogeneticprotein-7against high glucose-induced oxidative stress in mesangial cells.BiochemBiophys Res Commun,2009,382(2):292-297
[157] Marrero MB, Banes-Berceli AK, Stern DM, et al. Role of the JAK/STATsignalingpathway in diabetic nephropathy. Am J Physiol Renal Physiol,2006,290(4): F762~F768
[158] Rhyu DY,Yang Y,Ha H,et al.Role of reactive oxygen species in TGF-beta1-inducedmitogen-activated protein kinase activation and epithelialmesenchymal transition inrenal tubular epithelial cells.J Am Soc Nephrol,2005,16(3):667-675
[159] Nakajima T, Hasegawa G, Kamiuchi K, et al. Differ-ential regulation of intracellularredox state by extra-cellular matrix proteins in glomerular mesangial cells:Potentialrole in diabetic nephropathy[J]. Redox Rep,2006,11(5):223-230.
[160]薛华,孙喜明.蛋白激酶C与糖尿病肾病的关系[J].临床和实验医学杂志,2006,5(4):417.