JAKs/STATs信号转导通路在肾小球硬化中的作用及苦参碱对其影响的研究
|
摘要
以TGF-β、CTGF为代表的细胞因子在肾小球硬化过程中起重要作用，拮抗细胞因子的不良作用已成为防治肾小球硬化、延缓肾小球疾病进展中的重要环节。因此，加强对肾小球硬化相关细胞因子通路的研究是了解肾小球硬化机制，探索新的治疗方法和手段的重要途径。蛋白酪氨酸激酶(Janus Kinases／Just another Kinases，JAK)／信号传导子和转录激活子(signal transducers and activators of transcription，STAT)信号通路是一重要的细胞因子信号传导通路。在肾小球硬化过程中的不同阶段，炎症因子和肾小球硬化相关细胞因子的释放、ECM产生、肾固有细胞的活化及表型转化可能有不同的JAKs／STATs信号通路参与，目前尚无该方面的研究报道，本研究将探寻JAKs／STATs信号通路在肾小球硬化的作用，为进一步揭示肾小球硬化的生物学机制提供理论依据。
苦参是甘肃省的道地药材，系药用豆科槐属植物苦参(Sophora flavescens Ait)的干燥根，性寒味苦，具有清热燥湿，利尿的功效，始载于我国最早的药学文献《神农本草经》。苦参碱(matrine)和氧化苦参碱(oxymatrine)化学分子式分别为C_(15)H_(24)N_2O和C_(15)H_(24)N_2O_2，分子量分别为266和282，是苦参的主要活性成分，二者在一定条件下可以转化，有多方面的药理作用和功效，如抗炎、消肿利尿、免疫及生物反应调节作用等。近年来研究发现，苦参碱或氧化苦参碱具有抗肝脏纤维化和皮肤纤维的作用。
导师课题组前期研究工作已经从细胞实验和在体动物实验证实苦参碱在防治肾脏纤维化有一定作用。但其对肾小球硬化相关信号通路的影响和作用机制尚不十分清楚，为进一步探讨苦参碱防治肾脏纤维化的作用机理，本研究拟通过在体动物实验，探寻苦参碱对JAKs／STATs信号通路在阿霉素肾小球硬化大鼠中的作用。更加深入的了解苦参碱的作用机理，为开发新的防治肾纤维化的临床药物提供基础研究依据。
第一部分JAKs／STATs信号转导通路及其内源性抑制分子在肾小球硬化大鼠肾组织中的表达
目的：动态观察肾小球硬化大鼠模型病理变化过程中JAKs／STATs信号转导通路分子和内源性抑制分子SOCS、PIAS的表达，探讨肾小球硬化中JAKs／STATs信号转导通路分子和内源性抑制分子SOCS、PIAS的作用和可能机制，为进一步开展防治肾小球硬化研究提供实验依据。
方法：60只wistar大鼠随机分为两组：模型组和正常对照组。模型组采用右侧肾切除加1周后尾静脉注射阿霉素(5mg／kg)的方法建立肾小球硬化大鼠模型，设假手术组为正常对照组。2、4、6周分批处死每组各10只大鼠，检测24小时蛋白尿、血清肌酐和尿素氮的变化，免疫组化检测肾脏COL-Ⅳ、α-SMA表达，以确定成功制备肾小球硬化大鼠模型。采用免疫组化检测肾脏STAT1、STAT3的定位表达，western-blotting检测STAT1、P-STAT1、STAT3、P-STAT3蛋白的定量表达，采用实时荧光定量PCR(RT-PCR)技术观察JAK1、JAK2、STAT1、STAT3、SOCS1、SOCS3、PIAS1、PIAS3mRNA表达。
结果：
1．与对照组相比，模型组血清肌酐、尿素氮和24小时蛋白尿从2周起逐渐增高，至第6周明显高于对照组(P＜0.01)。组织病理学染色观察，模型组大鼠肾组织出现肾小球系膜基质中度增多，伴局灶节段性肾小球硬化，部分肾小球球囊粘连，肾间质可见炎性细胞侵润。肾小球硬化指数明显高于对照组(P＜0.01)。模型组COL-Ⅳ、α-SMA表达明显高于对照组及试验组(P＜0.05)，呈逐渐升高趋势；满肾小球硬化大鼠模型制备成功。
2．Western-boltting结果显示，模型组STAT1、P-STAT1蛋白随着病程的发展表达逐渐增高，第4、6周时同对照组相比差异有显著意义。STAT3、P-STAT3蛋白在第2周时表达增高，同对照组相比差异有显著意义，随后其表达逐渐降低。
3．经荧光定量RT-PCR反应结果显示，模型组JAK2mRNA的表达在第2、4周显著降低，于第6周增高，且较对照组相比差异具有统计学意义。模型组STAT3mRNA的表达呈现出在第2周时显著增高随后表达逐渐降低的趋势。模型组JAK1，STAT1，PIAS1mRNA的表达呈现出先增高后降低，再逐渐增高的趋势，且较对照组相比差异具有统计学意义。模型组SOCS1、SOCS3、PIAS3mRNA的表达在疾病过程中始终低于对照组，差异具有统计学意义。
结论：
1．JAK／STAT信号转导通路分子家族在大鼠肾小球硬化模型中的表达是不同的。不同的信号分子在肾小球硬化的早、中、晚期表达趋势并不相同，说明在肾小球硬化过程中激活该通路的细胞因子以及调节因素不同，各自对肾小球硬化的病理过程的形成起重要作用。
2．内源性抑制分子SOCS和PIAS家族在肾小球硬化过程中也有重要的作用，它们在不同的病理阶段表达不同，调节STAT分子的活化，它们的表达不足和过表达可能与肾小球硬化发展有关。
第二部分苦参碱对肾小球硬化大鼠肾组织JAKs／STATs信号转导通路分子及其内源性抑制分子影响的研究
目的观察苦参碱对阿霉素诱导的肾小球硬化大鼠JAKs／STATs分子变化的影响，探讨苦参碱防治肾小球硬化的机制。
方法雄性SPF级Wistar大鼠90只，体重180-200g，随机分成3组：对照组(假手术组)30只、模型组30只，苦参碱治疗组(苦参碱注射液肌肉注射25mg／kg．d)30只。检测各组术后第6周的尿蛋白、血清尿素氮、肌酐及肾组织病理改变，并应用免疫组织化学方法检测COL-Ⅳ、α-SMA、STAT1和STAT3蛋白质在肾皮质组织中的表达，以确定肾小球硬化模型的成功及苦参碱的防治效果。采用实时荧光定量PCR(RT-PCR)技术观察JAK1、JAK2、STAT1、STAT3、SOCS1、SOCS3、PIAS1、PIAS3mRNA表达。
结果
1．苦参碱治疗组的尿蛋白排泄量、血肌酐和尿素氮水平均低于模型组，肾小球硬化程度轻于模型组(P＜0.05)，肾皮质COL-Ⅳ、α-SMA蛋白表达也低于模型组(P＜0.05)。
2．苦参碱治疗组的STAT1蛋白水平于2周末高于模型组，在6周低于模型组(P＜0.05)，STAT3蛋白表达在个时间段均低于模型组(P＜0.05)。
3．经荧光定量PCR反应结果显示，和模型组相比苦参碱治疗组JAK2、STATI、STAT3、PIAS1mRNA表达降低，SOCS1、SOCS3、PIAS3mRNA表达显著增高
结论苦参碱对肾小球硬化大鼠模型肾脏病变有部分防护作用。苦参碱对肾小球硬化的防治是通过抑制JAK2、STAT1、STAT3、PIAS1分子，和增加SOCS1、SOCS3、PIAS3的表达起作用的。
The accumulating evidence suggests that cytokines such as transforminggrowth factorβ_1(TGFβ_1) and connective tissue growth factor (CTGF) plays akey role in the development of glomerulosclerosis (GS). Most of thosecytokines were produced by the proliferated glomerular mesangial cell (MsC).They can induce abnormal accumulation of extracellular matrix (ECM) and theresident cells-myofiblast transdifferentiation which contribute to theprogress of GS. The Janus kinase-signal transducers and activators oftranscription (JAKs/STATs) pathway is an essential intracellular mechanism ofcytokine actions and constitutes a link between activation of cell surfacereceptors and nuclear transcriptional event. Recent findings have indicated akey role of STAT1and STAT3 activation in a number of kidney diseases, and itis likely that STAT1 and STAT3 may represent new moleculars target for thetreatment. However, little is known about the pathogenic significance ofJAKs/STATs in GS. To better understand the pathogenic significance ofJAKs/STATs in GS and how the STAT s function is regulated, we carried outthis research.
Matrine (MT) and Oxymatrine (OMT) are the major quinolizidine alkaloidsin the roots of of traditional Chinese medical herb sophora flavescens ait. It isreported that OMT taken orally can be reduced to MT, which is moreabsorbable by intestinal bacteria. Basic and clinical research suggests thatoxymatrine and matrine have a variety of pharmacological activities, includinganti-cancer, anti-inflammatory, antipyretic, analgesic, anti-arrhythmia effectsand immune regulation, anti-virus properties, hepatocyte-protected effect andanti-hepatic fibrosis action.
Our long-term research had proved that matrine could significantly inhibitthe proliferation of rat glomerular mesangial cell, extracellular matrix and ndthe resident cells-myofiblast transdifferentiation in vitro and in vivo. But themechanism of matrine on glomerulosclerosis is still not clear. To explore the effect and probable mechanism of matrine on glomerulosclerosis, the changesof JAKs/STATs pathway molecules and endogenous feedback inhibitors wereobserved in the FSGS rat model. These results will provide clues for matrine tobe developed to prevent and treat glomerulosclerosis.
Part One: Expression of JAKs/STATs pathway molecules in ratmodel of glomerulosclerosis
Objective The purposes of this study were to dynamically measure thelevels of JAKs/STATs pathway molecules in glomerulosclerosis rat model andto assess their effect on the pathological process.
Medthods Sixty male Wistar rats were randomly divided into two groups:model group and normal control group. Adriamycin nephropathy was inducedby lateral nephrectomy at the right side and a single tail intravenous injection ofadriamycin (5mg/kg). Ten rats were sacrificed every 2 weeks in both groups.Immunohistochemistry was used to examine the expression ofα-SMA andCOL-IV. Western-boltting was used to examine the expression of STAT1,STAT3, P-STAT1, P-STAT3 and TGFβ1 protein. Finally, the expressions ofJAK1, JAK2, STAT1, STAT3, SOCS1, SOCS3, PIAS1 and PIAS3 mRNA weremeasured by real-time quantitative RT-PCR.
Resultsα-SMA, COL-IV and TGFβ1 protein expression graduallyincreased in model group, and much higher than normal control group at 6week. STAT1 and P-STAT1 protein expression in model group increased at 4week compared with the normal control group. STAT3 and P-STAT3 proteinexpression in model group increased at 2week. The mRNA level of JAK2,STAT1, STAT3, PIAS1 in model group was significantly increased comparedwith the normal control group and showed developing change. SOCS3 mRNAshow significantly increased compared with the normal control group in week2,then decreased. JAK1, SOCS1 and PIAS3 mRNA expression in model have a trend of initially increased and then decreased, and increased finally.
Conclusions JAKs/STATs singaling pathway and endogenous feedbackinhibitors may play an important role in the pathological process of rapid focalsegmental glomerulosclerosis in rat model.
Part Two: Investigation the effect of matrine on JAKs/STATspathway molecules in rat model of glomerulosclerosis
Objective To observe the effects of matrine on the levels of JAKs/STATspathway molecules in focal segmental glomerulosclerosis rat model and toexplore its mechanism.
Medthods The experiments were performed on 90 male Wistar rats. The ratswere randomly divided into 3 groups: normal control group, model group,matrine treatment group(25mg/kg·d). The rats of normal control group weresubjected to sham operation and were injected with normal saline via the tailvein one week later. The rats of the other groups were uninephrectomized andinjected with adriamycin (5 mg/kg) via the tail vein one week later. Matrinetreatment group were given by gastric perfusion from the first day after theoperation. The level of urinary protein, serum creatinine (Scr) and blood ureanitrogen (BUN) were measured at 6th week after the operation. The degree ofglomerular lesions were evaluated by masson stain. The expression ofCOL-IV、α-SMA, STAT1、STAT3 protein in glomerulus were examined byimmunohistochemistry.The expressions of JAK1, JAK2, STAT1, STAT3,SOCS1, SOCS3, PIAS1 and PIAS3 mRNA were measured by real-timequantitative RT-PCR.
Results Matrine not only reduced the excretion of urinary protein and thelevel of serum creatinine and BUN, but also significantly amelioratedglomerular sclerosis and COL-IV、α-SMA protein expression (P＜0.05,respectively). Decreased STAT1 protein level in matrine treatment was observed by week 6. Significantly decreased STAT3 protein level was noted inmatrine treatment group in the whole time. The expressions of JAK1, JAK2,STAT1 and STAT3 mRNA were decreased in matrine treatment group ascompared to the model group (P＜0.05). The expressions of SOCS1, SOCS3and PIAS3mRNA were increased in three treatment groups as compared tothe model group (P＜0.05).
Conclusions Matrine has a renoprotective effect on experimentalglomerulosclerosis in rats. The possible mechanism might relate tointervention of the JAKs/STATs signaling pathway.
苦参是甘肃省的道地药材，系药用豆科槐属植物苦参(Sophora flavescens Ait)的干燥根，性寒味苦，具有清热燥湿，利尿的功效，始载于我国最早的药学文献《神农本草经》。苦参碱(matrine)和氧化苦参碱(oxymatrine)化学分子式分别为C_(15)H_(24)N_2O和C_(15)H_(24)N_2O_2，分子量分别为266和282，是苦参的主要活性成分，二者在一定条件下可以转化，有多方面的药理作用和功效，如抗炎、消肿利尿、免疫及生物反应调节作用等。近年来研究发现，苦参碱或氧化苦参碱具有抗肝脏纤维化和皮肤纤维的作用。
导师课题组前期研究工作已经从细胞实验和在体动物实验证实苦参碱在防治肾脏纤维化有一定作用。但其对肾小球硬化相关信号通路的影响和作用机制尚不十分清楚，为进一步探讨苦参碱防治肾脏纤维化的作用机理，本研究拟通过在体动物实验，探寻苦参碱对JAKs／STATs信号通路在阿霉素肾小球硬化大鼠中的作用。更加深入的了解苦参碱的作用机理，为开发新的防治肾纤维化的临床药物提供基础研究依据。
第一部分JAKs／STATs信号转导通路及其内源性抑制分子在肾小球硬化大鼠肾组织中的表达
目的：动态观察肾小球硬化大鼠模型病理变化过程中JAKs／STATs信号转导通路分子和内源性抑制分子SOCS、PIAS的表达，探讨肾小球硬化中JAKs／STATs信号转导通路分子和内源性抑制分子SOCS、PIAS的作用和可能机制，为进一步开展防治肾小球硬化研究提供实验依据。
方法：60只wistar大鼠随机分为两组：模型组和正常对照组。模型组采用右侧肾切除加1周后尾静脉注射阿霉素(5mg／kg)的方法建立肾小球硬化大鼠模型，设假手术组为正常对照组。2、4、6周分批处死每组各10只大鼠，检测24小时蛋白尿、血清肌酐和尿素氮的变化，免疫组化检测肾脏COL-Ⅳ、α-SMA表达，以确定成功制备肾小球硬化大鼠模型。采用免疫组化检测肾脏STAT1、STAT3的定位表达，western-blotting检测STAT1、P-STAT1、STAT3、P-STAT3蛋白的定量表达，采用实时荧光定量PCR(RT-PCR)技术观察JAK1、JAK2、STAT1、STAT3、SOCS1、SOCS3、PIAS1、PIAS3mRNA表达。
结果：
1．与对照组相比，模型组血清肌酐、尿素氮和24小时蛋白尿从2周起逐渐增高，至第6周明显高于对照组(P＜0.01)。组织病理学染色观察，模型组大鼠肾组织出现肾小球系膜基质中度增多，伴局灶节段性肾小球硬化，部分肾小球球囊粘连，肾间质可见炎性细胞侵润。肾小球硬化指数明显高于对照组(P＜0.01)。模型组COL-Ⅳ、α-SMA表达明显高于对照组及试验组(P＜0.05)，呈逐渐升高趋势；满肾小球硬化大鼠模型制备成功。
2．Western-boltting结果显示，模型组STAT1、P-STAT1蛋白随着病程的发展表达逐渐增高，第4、6周时同对照组相比差异有显著意义。STAT3、P-STAT3蛋白在第2周时表达增高，同对照组相比差异有显著意义，随后其表达逐渐降低。
3．经荧光定量RT-PCR反应结果显示，模型组JAK2mRNA的表达在第2、4周显著降低，于第6周增高，且较对照组相比差异具有统计学意义。模型组STAT3mRNA的表达呈现出在第2周时显著增高随后表达逐渐降低的趋势。模型组JAK1，STAT1，PIAS1mRNA的表达呈现出先增高后降低，再逐渐增高的趋势，且较对照组相比差异具有统计学意义。模型组SOCS1、SOCS3、PIAS3mRNA的表达在疾病过程中始终低于对照组，差异具有统计学意义。
结论：
1．JAK／STAT信号转导通路分子家族在大鼠肾小球硬化模型中的表达是不同的。不同的信号分子在肾小球硬化的早、中、晚期表达趋势并不相同，说明在肾小球硬化过程中激活该通路的细胞因子以及调节因素不同，各自对肾小球硬化的病理过程的形成起重要作用。
2．内源性抑制分子SOCS和PIAS家族在肾小球硬化过程中也有重要的作用，它们在不同的病理阶段表达不同，调节STAT分子的活化，它们的表达不足和过表达可能与肾小球硬化发展有关。
第二部分苦参碱对肾小球硬化大鼠肾组织JAKs／STATs信号转导通路分子及其内源性抑制分子影响的研究
目的观察苦参碱对阿霉素诱导的肾小球硬化大鼠JAKs／STATs分子变化的影响，探讨苦参碱防治肾小球硬化的机制。
方法雄性SPF级Wistar大鼠90只，体重180-200g，随机分成3组：对照组(假手术组)30只、模型组30只，苦参碱治疗组(苦参碱注射液肌肉注射25mg／kg．d)30只。检测各组术后第6周的尿蛋白、血清尿素氮、肌酐及肾组织病理改变，并应用免疫组织化学方法检测COL-Ⅳ、α-SMA、STAT1和STAT3蛋白质在肾皮质组织中的表达，以确定肾小球硬化模型的成功及苦参碱的防治效果。采用实时荧光定量PCR(RT-PCR)技术观察JAK1、JAK2、STAT1、STAT3、SOCS1、SOCS3、PIAS1、PIAS3mRNA表达。
结果
1．苦参碱治疗组的尿蛋白排泄量、血肌酐和尿素氮水平均低于模型组，肾小球硬化程度轻于模型组(P＜0.05)，肾皮质COL-Ⅳ、α-SMA蛋白表达也低于模型组(P＜0.05)。
2．苦参碱治疗组的STAT1蛋白水平于2周末高于模型组，在6周低于模型组(P＜0.05)，STAT3蛋白表达在个时间段均低于模型组(P＜0.05)。
3．经荧光定量PCR反应结果显示，和模型组相比苦参碱治疗组JAK2、STATI、STAT3、PIAS1mRNA表达降低，SOCS1、SOCS3、PIAS3mRNA表达显著增高
结论苦参碱对肾小球硬化大鼠模型肾脏病变有部分防护作用。苦参碱对肾小球硬化的防治是通过抑制JAK2、STAT1、STAT3、PIAS1分子，和增加SOCS1、SOCS3、PIAS3的表达起作用的。
The accumulating evidence suggests that cytokines such as transforminggrowth factorβ_1(TGFβ_1) and connective tissue growth factor (CTGF) plays akey role in the development of glomerulosclerosis (GS). Most of thosecytokines were produced by the proliferated glomerular mesangial cell (MsC).They can induce abnormal accumulation of extracellular matrix (ECM) and theresident cells-myofiblast transdifferentiation which contribute to theprogress of GS. The Janus kinase-signal transducers and activators oftranscription (JAKs/STATs) pathway is an essential intracellular mechanism ofcytokine actions and constitutes a link between activation of cell surfacereceptors and nuclear transcriptional event. Recent findings have indicated akey role of STAT1and STAT3 activation in a number of kidney diseases, and itis likely that STAT1 and STAT3 may represent new moleculars target for thetreatment. However, little is known about the pathogenic significance ofJAKs/STATs in GS. To better understand the pathogenic significance ofJAKs/STATs in GS and how the STAT s function is regulated, we carried outthis research.
Matrine (MT) and Oxymatrine (OMT) are the major quinolizidine alkaloidsin the roots of of traditional Chinese medical herb sophora flavescens ait. It isreported that OMT taken orally can be reduced to MT, which is moreabsorbable by intestinal bacteria. Basic and clinical research suggests thatoxymatrine and matrine have a variety of pharmacological activities, includinganti-cancer, anti-inflammatory, antipyretic, analgesic, anti-arrhythmia effectsand immune regulation, anti-virus properties, hepatocyte-protected effect andanti-hepatic fibrosis action.
Our long-term research had proved that matrine could significantly inhibitthe proliferation of rat glomerular mesangial cell, extracellular matrix and ndthe resident cells-myofiblast transdifferentiation in vitro and in vivo. But themechanism of matrine on glomerulosclerosis is still not clear. To explore the effect and probable mechanism of matrine on glomerulosclerosis, the changesof JAKs/STATs pathway molecules and endogenous feedback inhibitors wereobserved in the FSGS rat model. These results will provide clues for matrine tobe developed to prevent and treat glomerulosclerosis.
Part One: Expression of JAKs/STATs pathway molecules in ratmodel of glomerulosclerosis
Objective The purposes of this study were to dynamically measure thelevels of JAKs/STATs pathway molecules in glomerulosclerosis rat model andto assess their effect on the pathological process.
Medthods Sixty male Wistar rats were randomly divided into two groups:model group and normal control group. Adriamycin nephropathy was inducedby lateral nephrectomy at the right side and a single tail intravenous injection ofadriamycin (5mg/kg). Ten rats were sacrificed every 2 weeks in both groups.Immunohistochemistry was used to examine the expression ofα-SMA andCOL-IV. Western-boltting was used to examine the expression of STAT1,STAT3, P-STAT1, P-STAT3 and TGFβ1 protein. Finally, the expressions ofJAK1, JAK2, STAT1, STAT3, SOCS1, SOCS3, PIAS1 and PIAS3 mRNA weremeasured by real-time quantitative RT-PCR.
Resultsα-SMA, COL-IV and TGFβ1 protein expression graduallyincreased in model group, and much higher than normal control group at 6week. STAT1 and P-STAT1 protein expression in model group increased at 4week compared with the normal control group. STAT3 and P-STAT3 proteinexpression in model group increased at 2week. The mRNA level of JAK2,STAT1, STAT3, PIAS1 in model group was significantly increased comparedwith the normal control group and showed developing change. SOCS3 mRNAshow significantly increased compared with the normal control group in week2,then decreased. JAK1, SOCS1 and PIAS3 mRNA expression in model have a trend of initially increased and then decreased, and increased finally.
Conclusions JAKs/STATs singaling pathway and endogenous feedbackinhibitors may play an important role in the pathological process of rapid focalsegmental glomerulosclerosis in rat model.
Part Two: Investigation the effect of matrine on JAKs/STATspathway molecules in rat model of glomerulosclerosis
Objective To observe the effects of matrine on the levels of JAKs/STATspathway molecules in focal segmental glomerulosclerosis rat model and toexplore its mechanism.
Medthods The experiments were performed on 90 male Wistar rats. The ratswere randomly divided into 3 groups: normal control group, model group,matrine treatment group(25mg/kg·d). The rats of normal control group weresubjected to sham operation and were injected with normal saline via the tailvein one week later. The rats of the other groups were uninephrectomized andinjected with adriamycin (5 mg/kg) via the tail vein one week later. Matrinetreatment group were given by gastric perfusion from the first day after theoperation. The level of urinary protein, serum creatinine (Scr) and blood ureanitrogen (BUN) were measured at 6th week after the operation. The degree ofglomerular lesions were evaluated by masson stain. The expression ofCOL-IV、α-SMA, STAT1、STAT3 protein in glomerulus were examined byimmunohistochemistry.The expressions of JAK1, JAK2, STAT1, STAT3,SOCS1, SOCS3, PIAS1 and PIAS3 mRNA were measured by real-timequantitative RT-PCR.
Results Matrine not only reduced the excretion of urinary protein and thelevel of serum creatinine and BUN, but also significantly amelioratedglomerular sclerosis and COL-IV、α-SMA protein expression (P＜0.05,respectively). Decreased STAT1 protein level in matrine treatment was observed by week 6. Significantly decreased STAT3 protein level was noted inmatrine treatment group in the whole time. The expressions of JAK1, JAK2,STAT1 and STAT3 mRNA were decreased in matrine treatment group ascompared to the model group (P＜0.05). The expressions of SOCS1, SOCS3and PIAS3mRNA were increased in three treatment groups as compared tothe model group (P＜0.05).
Conclusions Matrine has a renoprotective effect on experimentalglomerulosclerosis in rats. The possible mechanism might relate tointervention of the JAKs/STATs signaling pathway.
引文
1 Boffa JJ, Lu Y, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C. Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases. J Am Soc Nephrol 2003; 14 (5): 1132-44.
2 Chatziantoniou C, Boffa JJ, Tharaux PL, Flamant M, Ronco P, Dussaule JC. Progression and regression in renal vascular and glomerular fibrosis. International journal of experimental pathology 2004; 85 (1): 1-11.
3 Dumoulin A, Hill GS, Montseny JJ, Meyrier A. Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis. Am J Kidney Dis 2003; 41 (1): 38-48.
4 Couser WG, Johnson RJ. Mechanisms of progressive renal disease in glomerulonephritis. Am J Kidney Dis 1994; 23 (2): 193-8.
5 Eddy AA. Molecular basis of renal fibrosis [Pediatric nephrology (Berlin, Germany) 2000; 15 (3-4): 290-301.
6 Eddy AA. Molecular insights into renal interstitial fibrosis [J Am Soc Nephrol 1996; 7 (12): 2495-508.
7 Panzer U, Steinmetz OM, Stahl RA, Wolf G. Kidney diseases and chemokines [Curr Drug Targets 2006; 7 (1): 65-80.
8 Segerer S, Nelson PJ. Chemokines in renal diseases [TheScientificWorldJournal 2005; 5: 835-44.
9 Bottinger EP, Bitzer M. TGF-beta signaling in renal disease [J Am Soc Nephrol 2002; 13 (10): 2600-10.
10 Fox SW, Haque SJ, Lovibond AC, Chambers TJ. The possible role of TGF-beta-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment in vitro [J Immunol 2003; 170 (7): 3679-87.
11 Hayashida T, Decaestecker M, Schnaper HW. Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. Faseb J 2003; 17 (11): 1576-8.
12 Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC. TGF-beta signal transduction and mesangial cell fibrogenesis. American journal of physiology 2003; 284 (2): F243-52.
13 Wang S, Hirschberg R. Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. The Journal of biological chemistry 2004; 279 (22): 23200-6.
14 Crean JK, Furlong F, Finlay D, Mitchell D, Murphy M, Conway B, et al. Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization. Faseb J 2004; 18 (13): 1541-3.
15 Crean JK, Lappin D, Godson C, Brady HR. Connective tissue growth factor: an attractive therapeutic target in fibrotic renal disease [Expert opinion on therapeutic targets 2001; 5 (4): 519-30.
16 Furlong F, Crean J, Thornton L, O'Leary R, Murphy M, Martin F. Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose. American journal of physiology 2007; 292 (6): F1691-700.
17 Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney international 1998; 53 (4): 853-61.
18 Riser BL, Cortes P, DeNichilo M, Deshmukh PV, Chahal PS, Mohammed AK, et al. Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: preliminary report. Kidney international 2003; 64 (2): 451-8.
19 O'Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Molecular immunology 2007; 44 (10): 2497-506.
20 Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT [Science 2002; 296 (5573): 1653-55.
21 Chatterjee-Kishore M, van den Akker F, Stark GR. Association of STATs with relatives and friends. Trends in cell biology 2000; 10 (3): 106-11.
22 Albanesi C, Fairchild HR, Madonna S, Scarponi C, De Pita O, Leung DY, et al. IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol 2007; 179 (2): 984-92.
23 Cisowski J, Zarebski A, Koj A. IL-1-mediated inhibition of IL-6-induced STAT3 activation is modulated by IL-4, MAP kinase inhibitors and redox state of HepG2 cells. Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 2002; 40 (4): 341-5.
24 Van De Wiele CJ, Marino JH, Whetsell ME, Vo SS, Masengale RM, Teague TK. Loss of interferon-induced Statl phosphorylation in activated T cells. J Interferon Cytokine Res 2004; 24 (3): 169-78.
25 Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res 1999; 19 (6): 563-73.
26 Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, et al. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. The EMBO journal 1998; 17 (22): 6670-7.
27 Yanagita M, Arai H, Nakano T, Ohashi K, Mizuno K, Fukatsu A, et al. Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. The Journal of biological chemistry 2001; 276 (45): 42364-9.
28 陈香美 张五星．中药肾华对慢性肾炎大鼠肾组织Stat3表达及活化的影响．中国中西医结合杂志 2005：6(25)：66-70．
29 Amiri F, Shaw S, Wang X, Tang J, Waller JL, Eaton DC, et al. Angiotensin Ⅱ activation of the JAK/STAT pathway in mesangial cells is altered by high glucose. Kidney international 2002; 61(5): 1605-16.
30 Hishikawa K, Oemar BS, Nakaki T. Static pressure regulates connective tissue growth factor expression in human mesangial cells.The Journal of biological chemistry 2001; 276 (20): 16797-803.
31 Shi YH, Zhao S, Wang C, Li Y, Duan HJ. Fluvastatin inhibits activation of JAK and STAT proteins in diabetic rat glomeruli and mesangial cells under high glucose conditions. Acta pharmacologica Sinica 2007; 28 (12): 1938-46.
32 谭焕然，张宝恒．苦参碱抗炎症作用的实验研究．中国中西医结合杂志．1985；5(2)：108-10，69．
33 Cho CH, Chuang CY, Chen CF. Study of the Antipyretic Activity of Matrine. A Lupin Alkaloid Isolated from Sophora subprostrata. Planta medica 1986; 52 (5): 343-5.
34 Zhang BH, Wang NS, Li XJ, Kong XJ, Cai YL. [Anti-arrhythmic effects of matrine, pharmacologica Sinica 1990; 11 (3): 253-7.
35 Chuang CY, Xiao JG, Chiou GC. Ocular anti-inflammatory actions of matrine [Journal of ocular pharmacology 1987; 3 (2): 129-34.
36 Wang GL, Zhang SS, Li ZH, Liu SF. Relation of effects of matrine on rat vasa deferens to activation of calcium channels.Acta pharmacologica Sinica 1994; 15 (3): 279-81.
37 Hu ZL, Zhang JP, Yu XB, Lin W, Qian DH, Wan MB. Effect of matrine on lipopolysaccharides/D-galactosamine-induced hepatitis and tumor necrosis factor release from macrophages in vitro. Acta pharmacologica Sinica 1996; 17 (4): 351-3.
38 杨军军，高申孟，陈慧．苦参碱诱导多发性骨髓瘤细胞株RPMI8226凋亡的实验研究．中国实验血液学杂志2007；15(3)：515-8．
39 Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF, et al. Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Acta pharmacologica Sinica 2001; 22 (2): 183-6.
40 Kearns GL. Hepatic drug metabolism in cystic fibrosis: recent developments and future directions. The Annals of pharmacotherapy 1993; 27 (1): 74-9.
41 金玉，张宏文．苦参碱及氧化苦参碱的抗纤维化作用研究进展．中国中西医结合肾病杂志 2004；5(8)：493-494．
42 张宏文：金玉；苦参碱对大鼠肾小球硬化早期防护作用的实验研究。中华 儿科杂志 2004；42(10)：737-40．
43 陈晨，金玉．氧化苦参碱对阿霉素大鼠慢性肾纤维化组织中核因子-kB表达的影响 南方医科大学学报．2007：27(3)：345-348．
44 孔秀岩，金玉，李津玉．苦参素防治阿霉素肾病鼠肾小球硬化．第四军医大学学报 2006；27(23)：2159-2162．
45 Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. Journal of cellular biochemistry 2001; 81(1): 102-13.
46 Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, Mundel P, et al. Inhibitory smads and tgf-Beta signaling in glomerular cells. J Am Soc Nephrol 2002; 13(11): 2657-66.
47 Gupta S, Clarkson MR, Duggan J, Brady HR. Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney international 2000; 58 (4): 1389-99.
48 Wahab NA, Yevdokimova N, Weston BS, Roberts T, Li XJ, Brinkman H, et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. The Biochemical journal 2001; 359 (Pt 1): 77-87.
49 Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, et al. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 2000; 11(1): 25-38.
50 Nakamura T, Ebihara I, Fukui M, Osada S, Nagaoka I, Horikoshi S, et al. Messenger RNA expression for growth factors in glomeruli from focal glomerular sclerosis. Clinical immunology and immunopathology 1993; 66(1): 33-42.
51 Morita H, Shinzato T, David G, Mizutani A, Habuchi H, Fujita Y, et al. Basic fibroblast growth factor-binding domain of heparan sulfate in the human glomerulosclerosis and renal tubulointerstitial fibrosis. Laboratory investigation; a journal of technical methods and pathology 1994; 71 (4): 528-35.
52 Floege J, Kriz W, Schulze M, Susani M, Kerjaschki D, Mooney A, et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. The Journal of clinical investigation 1995; 96 (6): 2809-19.
53 李建军，陈香美，等．复方肾华片对5／6肾切除大鼠的疗效观察．中国中药杂志 2005；30(5)：377-81．
54 李建军，陈香美，等．复方肾华片对5／6肾切除大鼠肾组织巨噬细胞移行抑制因子的影响．中国中西医结合杂志 2005；25(2)：150-3．
55 Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. Bioessays 1999; 21(1): 47-52.
56 Hilton DJ. Negative regulators of cytokine signal transduction. Cell Mol Life Sci 1999; 55(12): 1568-77.
57 Starr R, Hilton DJ. SOCS: suppressors of cytokine signalling. The international journal of biochemistry & cell biology 1998; 30 (10): 1081-5.
58 Nicola NA, Greenhalgh CJ. The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. Experimental hematology 2000; 28 (10): 1105-12.
59 Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. Journal of cell science 2000; 113 (Pt 16): 2813-9.
60 Kile BT, Alexander WS. The suppressors of cytokine signalling (SOCS). Cell Mol Life Sci 2001; 58 (11): 1627-35.
61 Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98 (5): 597-608. eng.
62 Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Fikrig E, et al. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 2000; 13 (6): 805-15.
63 Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 2002; 17 (5): 583-91.
64 Dai X, Sayama K, Yamasaki K, Tohyama M, Shirakata Y, Hanakawa Y, et al. SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes. The Journal of investigative dermatology 2006; 126 (7): 1574-81.
65 Davey GM, Heath WR, Starr R. SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. Tissue antigens 2006; 67 (1): 1-9.
66 Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. The Journal of biological chemistry 2000; 275 (38): 29338-47.
67 Boisclair YR, Wang J, Shi J, Hurst KR, Ooi GT. Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1 beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. The Journal of biological chemistry 2000; 275 (6): 3841-7.
68 Tannahill GM, Elliott J, Barry AC, Hibbert L, Cacalano NA, Johnston JA. SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Molecular and cellular biology 2005; 25 (20): 9115-26.
69 Sommer U, Schmid C, Sobota RM, Lehmann U, Stevenson NJ, Johnston JA, et al. Mechanisms of SOCS3 phosphorylation upon interleukin-6 stimulation. Contributions of Src- and receptor-tyrosine kinases. The Journal of biological chemistry 2005; 280 (36): 31478-88.
70 Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, et al. SOCS1 and SOCS3 are targeted by hepatitis C virus core/gC1qR ligation to inhibit T-cell function. Journal of virology 2005; 79 (24): 15417-29.
71 Ben-Zvi T, Yayon A, Gertler A, Monsonego-Ornan E. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. Journal of cell science 2006; 119 (Pt 2): 380-7.
72 Baus D, Pfitzner E. Specific function of STAT3, SOCS1, and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma cells. International journal of cancer 2006; 118 (6): 1404-13.
73 Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences of the United States of America 1998; 95 (18): 10626-31.
74 Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997; 278 (5344): 1803-5.
75 Rogers RS, Horvath CM, Matunis MJ. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. The Journal of biological chemistry 2003; 278 (32): 30091-7.
76 Wormald S, Hilton DJ. Inhibitors of cytokine signal transduction. The Journal of biological chemistry 2004; 279 (2): 821-4.
77 Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell research 2006; 16 (2): 196-202.
78 Floege J, Johnson RJ, Couser WG. Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. The Clinical investigator 1992; 70 (9): 857-64.
79 王颖航，潘志，王耀献．肾络癥瘕分子病理基础的诠释．北京中医药大学学报 2006；29(5)：301-303
80 Kamei J, Xiao P, Ohsawa M, Kubo H, Higashiyama K, Takahashi H, et al. Antinociceptive effects of (+)-matrine in mice. European journal of pharmacology 1997; 337 (2-3): 223-6.
81 王晓红；黄圣凯．苦参碱及氧化苦参碱的药代动力学与药效动力学．药学学报 1992；27(8)：572-576
82 Ostendorf T, Rong S, Boor P, Wiedemann S, Kunter U, Haubold U, et al. Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17(4): 1054-62.
83 Dubey RK, Gillespie DG, Mi Z, Jackson EK. Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A(2B) receptors. Hypertension 2005; 46 (3): 628-34.
84 Floege J, Hudkins KL, Davis CL, Schwartz SM, Alpers CE. Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants. J Am Soc Nephrol 1998; 9 (2): 211-23.
85 Terada Y, Yamada T, Nakashima O, Sasaki S, Nonoguchi H, Tomita K, et al. Expression of PDGF and PDGF receptor mRNA in glomeruli in IgA nephropathy. J Am Soc Nephrol 1997; 8 (5): 817-9.
86 Floege J, Burns MW, Alpers CE, Yoshimura A, Pritzl P, Gordon K, et al. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney international 1992; 41 (2): 297-309.
87 Fellstrom B, Klareskog L, Heldin CH, Larsson E, Ronnstrand L, Terracio L, et al. Platelet-derived growth factor receptors in the kidney--upregulated expression in inflammation. Kidney international 1989; 36 (6): 1099-102.
88 Brabcova I, Kotsch K, Hribova P, Louzecka A, Bartosova K, Hyklova K, et al. Intrarenal gene expression of proinflammatory chemokines and cytokines in chronic proteinuric glomerulopathies. Physiological Research 2007; 56 (2): 221-26.
89 Kishida M, Urakaze M, Takata M, Nobata Y, Yamamoto N, Temaru R, et al. PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells. Exp Clin Endocr Diab 2005; 113 (7): 365-71.
90 Bakr A, Shokeir M, EI-Chenawi F, EI-Husseni F, Abdel-Rahman A, EI-Ashry R. Tumor necrosis factor-alpha production from mononuclear cells in nephrotic syndrome. Pediatric Nephrology 2003; 18 (6): 516-20.
91 Niemir ZI, Stein H, Dworacki G, Mundel P, Koehl N, Koch B, et al. Podocytes are the major source of IL-1 alpha and IL-1 beta in human glomerulonephritides. Kidney international 1997; 52 (2): 393-403.
92 赵志辉．系膜增殖性肾小球炎症、硬化过程中白细胞介素Ⅰ与转化生长因子β的mRNA基因表达．中华医学杂志 1992；72(4)：195-197
93 Higuchi A, Fujisawa M, Ueno K, Kamidono S. Elevation of urinary IL-1 beta levels during transplant associated nephropathy in rat model of the nephrotic syndrome. Urol Res 2002; 30 (3): 159-63.
94 Peters I, Tossidou I, Achenbach J, Woroniecki R, Mengel M, Park JK, et al. IGF-binding protein-3 modulates TGF-beta/BMP-signaling in glomerular podocytes. J Am Soc Nephrol 2006; 17 (6): 1644-56.
95 Fornoni A, Rosenzweig SA, Lenz O, Rivera A, Striker GE, Elliot SJ. Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. Endocrinology 2006; 147 (7): 3547-54.
96 Homey MJ, Shirley DW, Kurtz DT, Rosenzweig SA. Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor I. The American journal of physiology 1998; 274 (6 Pt 2): F1045-53.
97 Runyan CE, Schnaper HW, Poncelet AC. Smad3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells. American journal of physiology 2003; 285 (3): F413-22.
98 Antus B, Hamar P, Kokeny G, Szollosi Z, Mucsi I, Nemes Z, et al. Estradiol is nephroprotective in the rat remnant kidney. Nephrol Dial Transplant 2003; 18 (1): 54-61.
99 Oyama A, Muso E, Ono T, Matsushima H, Yashiro M, Suyama K, et al. Up-regulated TGF-beta mRNA expression in splenic T cells of high IgA-prone mice: a murine model of IgA nephropathy with glomerulosclerosis. Nephron 2001; 88 (4): 368-75.
100 Sodhi CP, Batlle D, Sahai A. Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney international 2000; 58 (2): 691-700.
101 Li J, Campanale NV, Liang RJ, Deane JA, Bertram JF, Ricardo SD. Inhibition of p38 mitogen-activated protein kinase and transforming growth factor-beta1/Smad signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy. The American journal of pathology 2006; 169 (5): 1527-40.
102 Krepinsky JC, Ingram AJ, Tang D, Wu D, Liu L, Scholey JW. Nitric oxide inhibits stretch-induced MAPK activation in mesangial cells through RhoA inactivation. J Am Soc Nephrol 2003; 14 (11): 2790-800.
103 Liu BF, Miyata S, Hirota Y, Higo S, Miyazaki H, Fukunaga M, et al. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney international 2003; 63 (3): 947-57.
104 Jaffa AA, Miller BS, Rosenzweig SA, Naidu PS, Velarde V, Mayfield RK. Bradykinin induces tubulin phosphorylation and nuclear translocation of MAP kinase in mesangial cells. The American journal of physiology 1997; 273 (6 Pt 2): F916-24.
105 Martinez-Salgado C, Fuentes-Calvo I, Garcia-Cenador B, Santos E, Lopez-Novoa JM. Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Experimental cell research 2006; 312 (11): 2093-106.
106 Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta physiologica Scandinavica 2005; 183 (1): 3-12.
107 Deambrosis I, Scalabrino E, Deregibus MC, Camussi G, Bussolati B. CD40-dependent activation of phosphatidylinositol 3-kinase/AKT pathway inhibits apoptosis of human cultured mesangial cells induced by oxidized LDL. International journal of immunopathology and pharmacology 2005; 18 (2): 327-37.
108 张宏：王湘玲；张艳玲；侯平；李寒；王海燕．小鼠Collectrin正反义真核表达载体的构建及其功能．北京大学学报(医学版)2004；36(2)：181-4．
109 李寒；张宏；王海燕．肾脏特异表达新基因Collectrin在大鼠5／6肾切除残余肾中的表达．中华医学杂志 2003；83(8)：684-7．
110 Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, et al. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. The Journal of biological chemistry 2001;276 (20): 17132-9.
111 Zhang Y, Zhang H, Hou P, Liang X, Li Z, Wang H. The novel gene AngRem104 downregulates glucocorticoid receptor expression and activates NF-kappaB in human mesangial cells. Biochem Biophys Res Commun 2008; 369 (4): 1057-60.
112 张艳玲；张宏；梁秀彬；侯平；王海燕．应用酵母双杂交系统筛选新基因AngRem104相关蛋白．北京大学学报(医学版)．2003；35(4)：369-72．
113 Liang XB, Zhang H, Zhou AY, Wang HY. Screening for functional genes related to a novel gene, AngRem104, in human mesangial cells by cDNA microarray. Biotechnology letters 2003; 25 (2): 139-42.
114 Liang X, Zhang H, Zhou A, Wang H. AngRem104, an angiotensin II-induced novel upregulated gene in human mesangial cells, is potentially involved in the regulation of fibronectin expression. J Am Soc Nephrol 2003; 14 (6): 1443-51.
115 Liang X, Zhang H, Zhou A, Hou P, Wang H. Screening and identification of the up-regulated genes in human mesangial cells exposed to angiotensin II. Hypertens Res 2003; 26 (3): 225-35.
116 Choi HJ, Lee BH, Cho HY, Moon KC, Ha IS, Nagata M, et al. Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism. Am J Kidney Dis 2008; 51 (5): 834-8.
117 Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, et al. Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 2005; 16 (12): 3694-701.
118 Kos CH, Le TC, Sinha S, Henderson JM, Kim SH, Sugimoto H, et al. Mice deficient in alpha-actinin-4 have severe glomerular disease. The Journal of clinical investigation 2003; 111 (11): 1683-90.
119 Pollak MR. The genetic basis of FSGS and steroid-resistant nephrosis. Seminars in nephrology 2003; 23 (2): 141-6.
120 Komatsuda A, Wakui H, Maki N, Kigawa A, Goto H, Ohtani H, et al. Analysis of mutations in alpha-actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis. Renal failure 2003; 25 (1): 87-93.
121 Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmentai glomerulosclerosis. Nature genetics 2000; 24 (3): 251-6. eng.
122 McKenzie LM, Hendrickson SL, Briggs WA, Dart RA, Korbet SM, Mokrzycki MH, et al. NPHS2 variation in sporadic focal segmentai glomerulosclerosis. J Am Soc Nephrol 2007; 18 (11): 2987-95.
123 He N, Zahirieh A, Mei Y, Lee B, Senthilnathan S, Wong B, et al. Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmentai glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2 (1): 31-7.
124 Di Duca M, Oleggini R, Sanna-Cherchi S, Pasquali L, Di Donato A, Parodi S, et al. Cis and trans regulatory elements in NPHS2 promoter: implications in proteinuria and progression of renal diseases.Kidney international 2006; 70 (7): 1332-41.
125 Monteiro EJ, Pereira AC, Pereira AB, Krieger JE, Mastroianni-Kirsztajn G. NPHS2 mutations in adult patients with primary focal segmentai glomerulosclerosis.Journal of nephrology 2006; 19 (3): 366-71.
126 Andreoli SP. Racial and ethnic differences in the incidence and progression of focal segmentai glomerulosclerosis in children. Advances in renal replacement therapy 2004; 11 (1): 105-9.
127 Rana K, Isbel N, Buzza M, Dagher H, Henning P, Kainer G, et al. Clinical, histopathologic, and genetic studies in nine families with focal segmentai glomerulosclerosis. Am J Kidney Dis 2003; 41 (6): 1170-8.
128 Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Will the addition of pentoxifylline reduce proteinuria in patients with diabetic glomerulosclerosis refractory to maximal doses of both an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker?. Journal of nephrology 2007; 20 (4): 410-6.
129 Futrakul N, Panichakul T, Butthep P, Futrakul P, Jetanalin P, Patumraj S, et al. Ganoderma lucidum suppresses endothelial cell cytotoxicity and proteinuria in persistent proteinuric focal segmentai glomerulosclerosis (FSGS) nephrosis. Clin Hemorheol Microcirc 2004; 31 (4): 267-72.
130 Han Z, Xing Y, Wang H, Liang X, Zhou J. Effects of the combined use of benazepril and valsartan on apoptosis in the kidney of rats with adriamycin-induced nephritic glomerulosclerosis. Journal of Huazhong University of Science and Technology Medical sciences.2004; 24 (3): 254-8.
131 Stoian M, Radulian G, Chitac D, Simion E, Stoica V. A clinical approach in regression of glomerulosclerosis. Romanian journal of internal medicine Revue roumaine de medecine interne 2007; 45 (2): 215-8. eng.
132 Yamamoto M, Fukui M, Shou I, Wang LN, Sekizuka K, Suzuki S, et al. Effects of treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AllRA) on renal function and glomerular injury in subtotal nephrectomized rats. Journal of clinical laboratory analysis 1997; 11 (1): 53-62. eng.
133 Allard J, Buleon M, Cellier E, Renaud I, Pecher C, Praddaude F, et al. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. American journal of physiology 2007; 293 (4): F1083-92. eng.
134 Buleon M, Allard J, Jaafar A, Praddaude F, Dickson Z, Ranera MT, et al. Pharmacological blockade of B2-kinin receptor reduces renal protective effect of Angiotensin-Converting Enzyme Inhibition in db/db mice model. American journal of physiology 2008.
135 Nakamura T, Obata J, Kimura H, Ohno S, Yoshida Y, Kawachi H, et al. Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis. Kidney international 1999; 55 (3): 877-89.
136 Yang J, Dai C, Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol 2002; 13 (10): 2464-77.
137 Tang SC, Leung JC, Chan LY, Eddy AA, Lai KN. Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy. Kidney international 2008; 73 (3): 288-99.
138 Asanuma K, Shirato I, Ishidoh K, Kominami E, Tomino Y. Selective modulation of the secretion of proteinases and their inhibitors by growth factors in cultured differentiated podocytes. Kidney international 2002; 62 (3): 822-31.
139 Buemi M, Nostro L, Crasci E, Barilla A, Cosentini V, Aloisi C, et al. Statins in nephrotic syndrome: a new weapon against tissue injury. Medicinal research reviews 2005; 25 (6): 587-609. eng.
140 McCarty MF. Adjuvant strategies for prevention of glomerulosclerosis. Medical hypotheses 2006; 67 (6): 1277-96. eng.
141 Oda H, Keane WF. Recent advances in statins and the kidney. Kidney Int Suppl 1999;71:S2-5. eng.
142 Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2 (5): 906-13.
143 Park HS, Bao L, Kim YJ, Cho IH, Lee CH, Hyun BH, et al. Pirfenidone suppressed the development of glomerulosclerosis in the FGS/Kist mouse. Journal of Korean medical science 2003; 18 (4): 527-33.
144 Cao Z, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, ef al. Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. Hypertension 2000; 36 (4): 561-8.
145 Clozel M, Hess P, Fischli W, Loffler BM, Zwacka RM, Reuter A, et al. Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease. Experimental gerontology 1999; 34 (8): 1007-15.
146 Dussaule JC, Tharaux PL, Boffa JJ, Fakhouri F, Ardaillou R, Chatziantoniou C. Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice. J Am Soc Nephrol 2000; 11 Suppl 16: S124-8.
2 Chatziantoniou C, Boffa JJ, Tharaux PL, Flamant M, Ronco P, Dussaule JC. Progression and regression in renal vascular and glomerular fibrosis. International journal of experimental pathology 2004; 85 (1): 1-11.
3 Dumoulin A, Hill GS, Montseny JJ, Meyrier A. Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis. Am J Kidney Dis 2003; 41 (1): 38-48.
4 Couser WG, Johnson RJ. Mechanisms of progressive renal disease in glomerulonephritis. Am J Kidney Dis 1994; 23 (2): 193-8.
5 Eddy AA. Molecular basis of renal fibrosis [Pediatric nephrology (Berlin, Germany) 2000; 15 (3-4): 290-301.
6 Eddy AA. Molecular insights into renal interstitial fibrosis [J Am Soc Nephrol 1996; 7 (12): 2495-508.
7 Panzer U, Steinmetz OM, Stahl RA, Wolf G. Kidney diseases and chemokines [Curr Drug Targets 2006; 7 (1): 65-80.
8 Segerer S, Nelson PJ. Chemokines in renal diseases [TheScientificWorldJournal 2005; 5: 835-44.
9 Bottinger EP, Bitzer M. TGF-beta signaling in renal disease [J Am Soc Nephrol 2002; 13 (10): 2600-10.
10 Fox SW, Haque SJ, Lovibond AC, Chambers TJ. The possible role of TGF-beta-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment in vitro [J Immunol 2003; 170 (7): 3679-87.
11 Hayashida T, Decaestecker M, Schnaper HW. Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. Faseb J 2003; 17 (11): 1576-8.
12 Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC. TGF-beta signal transduction and mesangial cell fibrogenesis. American journal of physiology 2003; 284 (2): F243-52.
13 Wang S, Hirschberg R. Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. The Journal of biological chemistry 2004; 279 (22): 23200-6.
14 Crean JK, Furlong F, Finlay D, Mitchell D, Murphy M, Conway B, et al. Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization. Faseb J 2004; 18 (13): 1541-3.
15 Crean JK, Lappin D, Godson C, Brady HR. Connective tissue growth factor: an attractive therapeutic target in fibrotic renal disease [Expert opinion on therapeutic targets 2001; 5 (4): 519-30.
16 Furlong F, Crean J, Thornton L, O'Leary R, Murphy M, Martin F. Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose. American journal of physiology 2007; 292 (6): F1691-700.
17 Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney international 1998; 53 (4): 853-61.
18 Riser BL, Cortes P, DeNichilo M, Deshmukh PV, Chahal PS, Mohammed AK, et al. Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: preliminary report. Kidney international 2003; 64 (2): 451-8.
19 O'Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Molecular immunology 2007; 44 (10): 2497-506.
20 Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT [Science 2002; 296 (5573): 1653-55.
21 Chatterjee-Kishore M, van den Akker F, Stark GR. Association of STATs with relatives and friends. Trends in cell biology 2000; 10 (3): 106-11.
22 Albanesi C, Fairchild HR, Madonna S, Scarponi C, De Pita O, Leung DY, et al. IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol 2007; 179 (2): 984-92.
23 Cisowski J, Zarebski A, Koj A. IL-1-mediated inhibition of IL-6-induced STAT3 activation is modulated by IL-4, MAP kinase inhibitors and redox state of HepG2 cells. Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 2002; 40 (4): 341-5.
24 Van De Wiele CJ, Marino JH, Whetsell ME, Vo SS, Masengale RM, Teague TK. Loss of interferon-induced Statl phosphorylation in activated T cells. J Interferon Cytokine Res 2004; 24 (3): 169-78.
25 Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res 1999; 19 (6): 563-73.
26 Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, et al. STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition. The EMBO journal 1998; 17 (22): 6670-7.
27 Yanagita M, Arai H, Nakano T, Ohashi K, Mizuno K, Fukatsu A, et al. Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. The Journal of biological chemistry 2001; 276 (45): 42364-9.
28 陈香美 张五星．中药肾华对慢性肾炎大鼠肾组织Stat3表达及活化的影响．中国中西医结合杂志 2005：6(25)：66-70．
29 Amiri F, Shaw S, Wang X, Tang J, Waller JL, Eaton DC, et al. Angiotensin Ⅱ activation of the JAK/STAT pathway in mesangial cells is altered by high glucose. Kidney international 2002; 61(5): 1605-16.
30 Hishikawa K, Oemar BS, Nakaki T. Static pressure regulates connective tissue growth factor expression in human mesangial cells.The Journal of biological chemistry 2001; 276 (20): 16797-803.
31 Shi YH, Zhao S, Wang C, Li Y, Duan HJ. Fluvastatin inhibits activation of JAK and STAT proteins in diabetic rat glomeruli and mesangial cells under high glucose conditions. Acta pharmacologica Sinica 2007; 28 (12): 1938-46.
32 谭焕然，张宝恒．苦参碱抗炎症作用的实验研究．中国中西医结合杂志．1985；5(2)：108-10，69．
33 Cho CH, Chuang CY, Chen CF. Study of the Antipyretic Activity of Matrine. A Lupin Alkaloid Isolated from Sophora subprostrata. Planta medica 1986; 52 (5): 343-5.
34 Zhang BH, Wang NS, Li XJ, Kong XJ, Cai YL. [Anti-arrhythmic effects of matrine, pharmacologica Sinica 1990; 11 (3): 253-7.
35 Chuang CY, Xiao JG, Chiou GC. Ocular anti-inflammatory actions of matrine [Journal of ocular pharmacology 1987; 3 (2): 129-34.
36 Wang GL, Zhang SS, Li ZH, Liu SF. Relation of effects of matrine on rat vasa deferens to activation of calcium channels.Acta pharmacologica Sinica 1994; 15 (3): 279-81.
37 Hu ZL, Zhang JP, Yu XB, Lin W, Qian DH, Wan MB. Effect of matrine on lipopolysaccharides/D-galactosamine-induced hepatitis and tumor necrosis factor release from macrophages in vitro. Acta pharmacologica Sinica 1996; 17 (4): 351-3.
38 杨军军，高申孟，陈慧．苦参碱诱导多发性骨髓瘤细胞株RPMI8226凋亡的实验研究．中国实验血液学杂志2007；15(3)：515-8．
39 Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF, et al. Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Acta pharmacologica Sinica 2001; 22 (2): 183-6.
40 Kearns GL. Hepatic drug metabolism in cystic fibrosis: recent developments and future directions. The Annals of pharmacotherapy 1993; 27 (1): 74-9.
41 金玉，张宏文．苦参碱及氧化苦参碱的抗纤维化作用研究进展．中国中西医结合肾病杂志 2004；5(8)：493-494．
42 张宏文：金玉；苦参碱对大鼠肾小球硬化早期防护作用的实验研究。中华 儿科杂志 2004；42(10)：737-40．
43 陈晨，金玉．氧化苦参碱对阿霉素大鼠慢性肾纤维化组织中核因子-kB表达的影响 南方医科大学学报．2007：27(3)：345-348．
44 孔秀岩，金玉，李津玉．苦参素防治阿霉素肾病鼠肾小球硬化．第四军医大学学报 2006；27(23)：2159-2162．
45 Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. Journal of cellular biochemistry 2001; 81(1): 102-13.
46 Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, Mundel P, et al. Inhibitory smads and tgf-Beta signaling in glomerular cells. J Am Soc Nephrol 2002; 13(11): 2657-66.
47 Gupta S, Clarkson MR, Duggan J, Brady HR. Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney international 2000; 58 (4): 1389-99.
48 Wahab NA, Yevdokimova N, Weston BS, Roberts T, Li XJ, Brinkman H, et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. The Biochemical journal 2001; 359 (Pt 1): 77-87.
49 Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, et al. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 2000; 11(1): 25-38.
50 Nakamura T, Ebihara I, Fukui M, Osada S, Nagaoka I, Horikoshi S, et al. Messenger RNA expression for growth factors in glomeruli from focal glomerular sclerosis. Clinical immunology and immunopathology 1993; 66(1): 33-42.
51 Morita H, Shinzato T, David G, Mizutani A, Habuchi H, Fujita Y, et al. Basic fibroblast growth factor-binding domain of heparan sulfate in the human glomerulosclerosis and renal tubulointerstitial fibrosis. Laboratory investigation; a journal of technical methods and pathology 1994; 71 (4): 528-35.
52 Floege J, Kriz W, Schulze M, Susani M, Kerjaschki D, Mooney A, et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. The Journal of clinical investigation 1995; 96 (6): 2809-19.
53 李建军，陈香美，等．复方肾华片对5／6肾切除大鼠的疗效观察．中国中药杂志 2005；30(5)：377-81．
54 李建军，陈香美，等．复方肾华片对5／6肾切除大鼠肾组织巨噬细胞移行抑制因子的影响．中国中西医结合杂志 2005；25(2)：150-3．
55 Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. Bioessays 1999; 21(1): 47-52.
56 Hilton DJ. Negative regulators of cytokine signal transduction. Cell Mol Life Sci 1999; 55(12): 1568-77.
57 Starr R, Hilton DJ. SOCS: suppressors of cytokine signalling. The international journal of biochemistry & cell biology 1998; 30 (10): 1081-5.
58 Nicola NA, Greenhalgh CJ. The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. Experimental hematology 2000; 28 (10): 1105-12.
59 Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. Journal of cell science 2000; 113 (Pt 16): 2813-9.
60 Kile BT, Alexander WS. The suppressors of cytokine signalling (SOCS). Cell Mol Life Sci 2001; 58 (11): 1627-35.
61 Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98 (5): 597-608. eng.
62 Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Fikrig E, et al. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 2000; 13 (6): 805-15.
63 Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 2002; 17 (5): 583-91.
64 Dai X, Sayama K, Yamasaki K, Tohyama M, Shirakata Y, Hanakawa Y, et al. SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes. The Journal of investigative dermatology 2006; 126 (7): 1574-81.
65 Davey GM, Heath WR, Starr R. SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. Tissue antigens 2006; 67 (1): 1-9.
66 Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. The Journal of biological chemistry 2000; 275 (38): 29338-47.
67 Boisclair YR, Wang J, Shi J, Hurst KR, Ooi GT. Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1 beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. The Journal of biological chemistry 2000; 275 (6): 3841-7.
68 Tannahill GM, Elliott J, Barry AC, Hibbert L, Cacalano NA, Johnston JA. SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Molecular and cellular biology 2005; 25 (20): 9115-26.
69 Sommer U, Schmid C, Sobota RM, Lehmann U, Stevenson NJ, Johnston JA, et al. Mechanisms of SOCS3 phosphorylation upon interleukin-6 stimulation. Contributions of Src- and receptor-tyrosine kinases. The Journal of biological chemistry 2005; 280 (36): 31478-88.
70 Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, et al. SOCS1 and SOCS3 are targeted by hepatitis C virus core/gC1qR ligation to inhibit T-cell function. Journal of virology 2005; 79 (24): 15417-29.
71 Ben-Zvi T, Yayon A, Gertler A, Monsonego-Ornan E. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. Journal of cell science 2006; 119 (Pt 2): 380-7.
72 Baus D, Pfitzner E. Specific function of STAT3, SOCS1, and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma cells. International journal of cancer 2006; 118 (6): 1404-13.
73 Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences of the United States of America 1998; 95 (18): 10626-31.
74 Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997; 278 (5344): 1803-5.
75 Rogers RS, Horvath CM, Matunis MJ. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. The Journal of biological chemistry 2003; 278 (32): 30091-7.
76 Wormald S, Hilton DJ. Inhibitors of cytokine signal transduction. The Journal of biological chemistry 2004; 279 (2): 821-4.
77 Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell research 2006; 16 (2): 196-202.
78 Floege J, Johnson RJ, Couser WG. Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. The Clinical investigator 1992; 70 (9): 857-64.
79 王颖航，潘志，王耀献．肾络癥瘕分子病理基础的诠释．北京中医药大学学报 2006；29(5)：301-303
80 Kamei J, Xiao P, Ohsawa M, Kubo H, Higashiyama K, Takahashi H, et al. Antinociceptive effects of (+)-matrine in mice. European journal of pharmacology 1997; 337 (2-3): 223-6.
81 王晓红；黄圣凯．苦参碱及氧化苦参碱的药代动力学与药效动力学．药学学报 1992；27(8)：572-576
82 Ostendorf T, Rong S, Boor P, Wiedemann S, Kunter U, Haubold U, et al. Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17(4): 1054-62.
83 Dubey RK, Gillespie DG, Mi Z, Jackson EK. Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A(2B) receptors. Hypertension 2005; 46 (3): 628-34.
84 Floege J, Hudkins KL, Davis CL, Schwartz SM, Alpers CE. Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants. J Am Soc Nephrol 1998; 9 (2): 211-23.
85 Terada Y, Yamada T, Nakashima O, Sasaki S, Nonoguchi H, Tomita K, et al. Expression of PDGF and PDGF receptor mRNA in glomeruli in IgA nephropathy. J Am Soc Nephrol 1997; 8 (5): 817-9.
86 Floege J, Burns MW, Alpers CE, Yoshimura A, Pritzl P, Gordon K, et al. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney international 1992; 41 (2): 297-309.
87 Fellstrom B, Klareskog L, Heldin CH, Larsson E, Ronnstrand L, Terracio L, et al. Platelet-derived growth factor receptors in the kidney--upregulated expression in inflammation. Kidney international 1989; 36 (6): 1099-102.
88 Brabcova I, Kotsch K, Hribova P, Louzecka A, Bartosova K, Hyklova K, et al. Intrarenal gene expression of proinflammatory chemokines and cytokines in chronic proteinuric glomerulopathies. Physiological Research 2007; 56 (2): 221-26.
89 Kishida M, Urakaze M, Takata M, Nobata Y, Yamamoto N, Temaru R, et al. PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells. Exp Clin Endocr Diab 2005; 113 (7): 365-71.
90 Bakr A, Shokeir M, EI-Chenawi F, EI-Husseni F, Abdel-Rahman A, EI-Ashry R. Tumor necrosis factor-alpha production from mononuclear cells in nephrotic syndrome. Pediatric Nephrology 2003; 18 (6): 516-20.
91 Niemir ZI, Stein H, Dworacki G, Mundel P, Koehl N, Koch B, et al. Podocytes are the major source of IL-1 alpha and IL-1 beta in human glomerulonephritides. Kidney international 1997; 52 (2): 393-403.
92 赵志辉．系膜增殖性肾小球炎症、硬化过程中白细胞介素Ⅰ与转化生长因子β的mRNA基因表达．中华医学杂志 1992；72(4)：195-197
93 Higuchi A, Fujisawa M, Ueno K, Kamidono S. Elevation of urinary IL-1 beta levels during transplant associated nephropathy in rat model of the nephrotic syndrome. Urol Res 2002; 30 (3): 159-63.
94 Peters I, Tossidou I, Achenbach J, Woroniecki R, Mengel M, Park JK, et al. IGF-binding protein-3 modulates TGF-beta/BMP-signaling in glomerular podocytes. J Am Soc Nephrol 2006; 17 (6): 1644-56.
95 Fornoni A, Rosenzweig SA, Lenz O, Rivera A, Striker GE, Elliot SJ. Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. Endocrinology 2006; 147 (7): 3547-54.
96 Homey MJ, Shirley DW, Kurtz DT, Rosenzweig SA. Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor I. The American journal of physiology 1998; 274 (6 Pt 2): F1045-53.
97 Runyan CE, Schnaper HW, Poncelet AC. Smad3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells. American journal of physiology 2003; 285 (3): F413-22.
98 Antus B, Hamar P, Kokeny G, Szollosi Z, Mucsi I, Nemes Z, et al. Estradiol is nephroprotective in the rat remnant kidney. Nephrol Dial Transplant 2003; 18 (1): 54-61.
99 Oyama A, Muso E, Ono T, Matsushima H, Yashiro M, Suyama K, et al. Up-regulated TGF-beta mRNA expression in splenic T cells of high IgA-prone mice: a murine model of IgA nephropathy with glomerulosclerosis. Nephron 2001; 88 (4): 368-75.
100 Sodhi CP, Batlle D, Sahai A. Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney international 2000; 58 (2): 691-700.
101 Li J, Campanale NV, Liang RJ, Deane JA, Bertram JF, Ricardo SD. Inhibition of p38 mitogen-activated protein kinase and transforming growth factor-beta1/Smad signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy. The American journal of pathology 2006; 169 (5): 1527-40.
102 Krepinsky JC, Ingram AJ, Tang D, Wu D, Liu L, Scholey JW. Nitric oxide inhibits stretch-induced MAPK activation in mesangial cells through RhoA inactivation. J Am Soc Nephrol 2003; 14 (11): 2790-800.
103 Liu BF, Miyata S, Hirota Y, Higo S, Miyazaki H, Fukunaga M, et al. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney international 2003; 63 (3): 947-57.
104 Jaffa AA, Miller BS, Rosenzweig SA, Naidu PS, Velarde V, Mayfield RK. Bradykinin induces tubulin phosphorylation and nuclear translocation of MAP kinase in mesangial cells. The American journal of physiology 1997; 273 (6 Pt 2): F916-24.
105 Martinez-Salgado C, Fuentes-Calvo I, Garcia-Cenador B, Santos E, Lopez-Novoa JM. Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Experimental cell research 2006; 312 (11): 2093-106.
106 Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta physiologica Scandinavica 2005; 183 (1): 3-12.
107 Deambrosis I, Scalabrino E, Deregibus MC, Camussi G, Bussolati B. CD40-dependent activation of phosphatidylinositol 3-kinase/AKT pathway inhibits apoptosis of human cultured mesangial cells induced by oxidized LDL. International journal of immunopathology and pharmacology 2005; 18 (2): 327-37.
108 张宏：王湘玲；张艳玲；侯平；李寒；王海燕．小鼠Collectrin正反义真核表达载体的构建及其功能．北京大学学报(医学版)2004；36(2)：181-4．
109 李寒；张宏；王海燕．肾脏特异表达新基因Collectrin在大鼠5／6肾切除残余肾中的表达．中华医学杂志 2003；83(8)：684-7．
110 Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, et al. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. The Journal of biological chemistry 2001;276 (20): 17132-9.
111 Zhang Y, Zhang H, Hou P, Liang X, Li Z, Wang H. The novel gene AngRem104 downregulates glucocorticoid receptor expression and activates NF-kappaB in human mesangial cells. Biochem Biophys Res Commun 2008; 369 (4): 1057-60.
112 张艳玲；张宏；梁秀彬；侯平；王海燕．应用酵母双杂交系统筛选新基因AngRem104相关蛋白．北京大学学报(医学版)．2003；35(4)：369-72．
113 Liang XB, Zhang H, Zhou AY, Wang HY. Screening for functional genes related to a novel gene, AngRem104, in human mesangial cells by cDNA microarray. Biotechnology letters 2003; 25 (2): 139-42.
114 Liang X, Zhang H, Zhou A, Wang H. AngRem104, an angiotensin II-induced novel upregulated gene in human mesangial cells, is potentially involved in the regulation of fibronectin expression. J Am Soc Nephrol 2003; 14 (6): 1443-51.
115 Liang X, Zhang H, Zhou A, Hou P, Wang H. Screening and identification of the up-regulated genes in human mesangial cells exposed to angiotensin II. Hypertens Res 2003; 26 (3): 225-35.
116 Choi HJ, Lee BH, Cho HY, Moon KC, Ha IS, Nagata M, et al. Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism. Am J Kidney Dis 2008; 51 (5): 834-8.
117 Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, et al. Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 2005; 16 (12): 3694-701.
118 Kos CH, Le TC, Sinha S, Henderson JM, Kim SH, Sugimoto H, et al. Mice deficient in alpha-actinin-4 have severe glomerular disease. The Journal of clinical investigation 2003; 111 (11): 1683-90.
119 Pollak MR. The genetic basis of FSGS and steroid-resistant nephrosis. Seminars in nephrology 2003; 23 (2): 141-6.
120 Komatsuda A, Wakui H, Maki N, Kigawa A, Goto H, Ohtani H, et al. Analysis of mutations in alpha-actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis. Renal failure 2003; 25 (1): 87-93.
121 Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmentai glomerulosclerosis. Nature genetics 2000; 24 (3): 251-6. eng.
122 McKenzie LM, Hendrickson SL, Briggs WA, Dart RA, Korbet SM, Mokrzycki MH, et al. NPHS2 variation in sporadic focal segmentai glomerulosclerosis. J Am Soc Nephrol 2007; 18 (11): 2987-95.
123 He N, Zahirieh A, Mei Y, Lee B, Senthilnathan S, Wong B, et al. Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmentai glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2 (1): 31-7.
124 Di Duca M, Oleggini R, Sanna-Cherchi S, Pasquali L, Di Donato A, Parodi S, et al. Cis and trans regulatory elements in NPHS2 promoter: implications in proteinuria and progression of renal diseases.Kidney international 2006; 70 (7): 1332-41.
125 Monteiro EJ, Pereira AC, Pereira AB, Krieger JE, Mastroianni-Kirsztajn G. NPHS2 mutations in adult patients with primary focal segmentai glomerulosclerosis.Journal of nephrology 2006; 19 (3): 366-71.
126 Andreoli SP. Racial and ethnic differences in the incidence and progression of focal segmentai glomerulosclerosis in children. Advances in renal replacement therapy 2004; 11 (1): 105-9.
127 Rana K, Isbel N, Buzza M, Dagher H, Henning P, Kainer G, et al. Clinical, histopathologic, and genetic studies in nine families with focal segmentai glomerulosclerosis. Am J Kidney Dis 2003; 41 (6): 1170-8.
128 Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Will the addition of pentoxifylline reduce proteinuria in patients with diabetic glomerulosclerosis refractory to maximal doses of both an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker?. Journal of nephrology 2007; 20 (4): 410-6.
129 Futrakul N, Panichakul T, Butthep P, Futrakul P, Jetanalin P, Patumraj S, et al. Ganoderma lucidum suppresses endothelial cell cytotoxicity and proteinuria in persistent proteinuric focal segmentai glomerulosclerosis (FSGS) nephrosis. Clin Hemorheol Microcirc 2004; 31 (4): 267-72.
130 Han Z, Xing Y, Wang H, Liang X, Zhou J. Effects of the combined use of benazepril and valsartan on apoptosis in the kidney of rats with adriamycin-induced nephritic glomerulosclerosis. Journal of Huazhong University of Science and Technology Medical sciences.2004; 24 (3): 254-8.
131 Stoian M, Radulian G, Chitac D, Simion E, Stoica V. A clinical approach in regression of glomerulosclerosis. Romanian journal of internal medicine Revue roumaine de medecine interne 2007; 45 (2): 215-8. eng.
132 Yamamoto M, Fukui M, Shou I, Wang LN, Sekizuka K, Suzuki S, et al. Effects of treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AllRA) on renal function and glomerular injury in subtotal nephrectomized rats. Journal of clinical laboratory analysis 1997; 11 (1): 53-62. eng.
133 Allard J, Buleon M, Cellier E, Renaud I, Pecher C, Praddaude F, et al. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. American journal of physiology 2007; 293 (4): F1083-92. eng.
134 Buleon M, Allard J, Jaafar A, Praddaude F, Dickson Z, Ranera MT, et al. Pharmacological blockade of B2-kinin receptor reduces renal protective effect of Angiotensin-Converting Enzyme Inhibition in db/db mice model. American journal of physiology 2008.
135 Nakamura T, Obata J, Kimura H, Ohno S, Yoshida Y, Kawachi H, et al. Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis. Kidney international 1999; 55 (3): 877-89.
136 Yang J, Dai C, Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol 2002; 13 (10): 2464-77.
137 Tang SC, Leung JC, Chan LY, Eddy AA, Lai KN. Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy. Kidney international 2008; 73 (3): 288-99.
138 Asanuma K, Shirato I, Ishidoh K, Kominami E, Tomino Y. Selective modulation of the secretion of proteinases and their inhibitors by growth factors in cultured differentiated podocytes. Kidney international 2002; 62 (3): 822-31.
139 Buemi M, Nostro L, Crasci E, Barilla A, Cosentini V, Aloisi C, et al. Statins in nephrotic syndrome: a new weapon against tissue injury. Medicinal research reviews 2005; 25 (6): 587-609. eng.
140 McCarty MF. Adjuvant strategies for prevention of glomerulosclerosis. Medical hypotheses 2006; 67 (6): 1277-96. eng.
141 Oda H, Keane WF. Recent advances in statins and the kidney. Kidney Int Suppl 1999;71:S2-5. eng.
142 Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2 (5): 906-13.
143 Park HS, Bao L, Kim YJ, Cho IH, Lee CH, Hyun BH, et al. Pirfenidone suppressed the development of glomerulosclerosis in the FGS/Kist mouse. Journal of Korean medical science 2003; 18 (4): 527-33.
144 Cao Z, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, ef al. Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. Hypertension 2000; 36 (4): 561-8.
145 Clozel M, Hess P, Fischli W, Loffler BM, Zwacka RM, Reuter A, et al. Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease. Experimental gerontology 1999; 34 (8): 1007-15.
146 Dussaule JC, Tharaux PL, Boffa JJ, Fakhouri F, Ardaillou R, Chatziantoniou C. Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice. J Am Soc Nephrol 2000; 11 Suppl 16: S124-8.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |