糖尿病肾病肾小球硬化机制的比较蛋白质组学研究
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摘要
目的：
糖尿病肾病(Diabetic nephropathy, DN)是糖尿病常见的微血管并发症,它不仅是慢性肾功能衰竭患者肾移植的主要原因,还能大幅增加糖尿病患者心血管疾病的死亡率。肾小球硬化是1型与2型DN共同的特征性肾脏病理改变。DN发病机制非常复杂,涉及氧化应激、多元醇通路激活、糖基化终末产物沉积、血流动力学改变及诸多细胞因子异常等因素,为了深入揭示DN肾小球硬化的病理机制,本研究采用蛋白质组学技术,以体内与体外实验相结合,通过自发型2型DN模型OLETF大鼠肾皮质胞浆和胞膜亚差异蛋白质组学研究和高糖环境下大鼠肾小球系膜细胞动态差异蛋白质组学研究,探讨DN时肾小球硬化发病过程中蛋白质组学变化规律,以期更加深入理解DN肾小球硬化的发生机理。
方法：
1.自发型2型DN模型OLETF大鼠差异蛋白质组学研究
OLETF大鼠和遗传背景相似但不发病的LETO大鼠各7只用于本实验。实验中OLETF大鼠血糖及尿蛋白排泄呈渐进性升高,出现肾小球硬化及间质纤维化等类似于人类2型DN的肾脏病理改变。动物在36周龄时处死取材,分离肾皮质,分别提取胞浆和胞膜总蛋白。获得的蛋白样品经双向电泳分离,胶体考马斯亮蓝染色显示。扫描输入计算机,用图像分析软件ImageMaster 6.0对凝胶进行分析,差异蛋白判定标准为：该蛋白点在LETO和OLETF两组间有统计学差异(两组蛋白点的volume%先经方差不齐t检验获得p,后经FDR校正后p<0.05),且volume%值变化超过2倍。将凝胶中的差异蛋白点切出,经胶内胰蛋白酶解和MALDI-TOF-MS获得肽质量指纹谱并进行Mascot对蛋白质进行分析。利用GoMinerTM、BINGO软件对差异蛋白质进行Gene Ontology(GO)分类和过度表达分析。对发现磷酸修饰的蛋白进行进一步的同源性和磷酸化位点保守性分析。
2.高糖环境下大鼠肾小球系膜细胞动态差异蛋白质组学研究
原代分离培养并传至第5代的大鼠肾小球系膜细胞分别置含5.5mM(正常对照组,NC组)和30mM葡萄糖(高糖组,HG组)培养基中,分别培养0h、8h、16h、72h、25day,提取细胞总蛋白。蛋白样品经双向电泳技术分离,胶体考马斯亮蓝显示,差异蛋白分析、判定,利用MALDI-TOF-MS获得肽指纹图谱进行蛋白鉴定,对凝胶上多个蛋白点代表同一种蛋白质的肽指纹图谱进行磷酸化修饰分析,对差异蛋白进行GO功能分类及过度表达分析。从IntAct Web Service Clien获取差异蛋白质的相互作用网路,用Cytoscape显示,并用MCODE分析。
结果：
1.描述了36周龄OLETF和LETO大鼠肾皮质胞浆和胞膜蛋白的差异蛋白质组学变化。与LETO大鼠相比OLETF大鼠肾皮质胞浆蛋白中9个蛋白点(Gapdh, Qdpr, Fah, similar to Protein C14orf159 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl)下调,8个蛋白点(Qdpr, Ephx2, Fthfd, Tf, Naprtl, Idh1, Fah, Cryab)上调。胞膜蛋白中11个蛋白点(Uqcrfsl, Nrnll, Pbld, LOC683519, Calbl, Acadsb, Dmgdh, Etfb)下调,10个蛋白点(LOC683519, Qdpr, GMPK, Etfb, Uqcrfsl, Fah, Dmgdh, Gpx3, cytokeratin 8 polypeptide)上调。这些差异蛋白主要定位在胞浆、线粒体和细胞小泡。能够和离子、维生素、蛋白结合,其分子功能主要和氧化还原活性、电子传递、转运、抗氧化有关,主要参与细胞信号传导、细胞凋亡、应激反应和芳香族氨基酸、氧和活性氧代谢过程。其参与的生物学过程包括氧化还原、羧酸代谢、一元羧酸代谢、急性炎症反应、应激反应、脂肪酸代谢过度表达等。研究中发现多个不同的点代表相同的蛋白质,提示不同的转录版本或不同的翻译后修饰在DN发病过程中有重要作用。初步判断Qdpr, Ephx2、LOC683519、GMPK在DN发病过程中发生了磷酸化修饰的改变。Ephx2同源性较高,Thr-50、Thr-59、Ser-70在人、小鼠、大鼠中保守性较高。
2.描述了高糖环境对肾小球系膜细胞影响的蛋白质组学动态变化。细胞蛋白质组学结果分析发现28个差异蛋白点,其中在8h和16h2个蛋白点表达上调(Rcn2, Hspb1),24个蛋白点(Tcpl, Wdrl, Cct2, Eno1, Adss, Eef1g, Idhl, Pcbpl, Akrlbl, rCG53488, Pgam1, Psma6, Psmb7, Prdx6, Gstpl, Stmn1, Sodl, Krt2-7, Hmgb1, Serpinb9)表达下调,72小时2个蛋白点(Psma6, Hmgbl)表达下调,25天有2个蛋白点(Pdia3, Idh3a)表达上调。差异表达的蛋白主要定位在胞浆、胞核、细胞骨架、线粒体和内质网上,能与蛋白、核酸、离子结合,其分子功能以抗氧化活性、氧化还原活性、水解酶活性、异构酶活性为主；并参与细胞信号、细胞周期、凋亡、细胞增殖、细胞碳水化合物代谢、DNA代谢、RNA代谢、蛋白质代谢、氧和活性氧代谢等多种生物过程。GO过度表达和蛋白相互作用分析发现差异蛋白不仅和已知在DN发病中起到重要作用的糖代谢、氧化应激、分子伴侣有关,还和蛋白酶体相关的蛋白降解过程密切相关。
结论：
1.本研究结果发现与基因背景类似的正常LETO大鼠相比糖尿病肾病大鼠OLETF大鼠中Qdpr、Ephx2、Fah、Fthfd、p55 protein等蛋白表达丰度或磷酸化修饰的改变,尤其是发现体内有着重要功能的Ephx2存在磷酸化修饰,且在糖尿病肾病下发生了磷酸化修饰的改变。提示在DN肾小球硬化过程中,许多蛋白不仅存在丰度变化,还存在转录后修饰变化。这些发现为DN肾小球硬化机理研究提供新的思路。
2.本研究结果发现高糖环境下系膜细胞PCBP1、HMGB1、Psma6、Psmb7、Prdx6、Rcn2、Serpinb9等蛋白表达丰度发生了动态改变。通过信息生物学研究发现除了已知的通路外,蛋白酶体通路也发生了改变,提示该通路与高糖环境下的肾小球系膜细胞增殖、肥大有着重要作用。这些发现可能为DN肾小球硬化机制研究提供新的思路。
Objective:Diabetic nephropathy is the leading cause of end stage renal disease, and is associated with increased cardiovascular mortality. The major renal pathological changes of diabetic nephropathy both developed from type 1 and type 2 diabetes are glomerular sclerosis. The major mechanism of diabetic nephropathy is not clear up to now, although oxidative stress, polyol pathway activation, advanced glycation end products, hemodynamics and various cytokines are presumed to be the main culprits of development of diabetic nephropathy. To explore the pathophysiologic mechanisms of diabetic nephropathy in depth, and improve our understanding of DN pathogenesis, proteomics strategy was performed to screen for dynamic proteomics profile of mesangial cells in response to high glucose condition and global changes of renal cortex protein expression in OLETF and LETO rats.
Methods:
1. Differential proteomics study of spontaneous type 2 diabetes model of OLETF and LETO rats.
Spontaneous diabetic rat of OLETF and healthy control rats with the same genetic background LETO rats were used in this experiment. OLETF rats developed hyperglycemia, progressive increase of urinary protein excretion and glomeruloscerosis. OLETF and LETO rats were sacrificed at the age of 36 weeks, and the renal cortical total membrane and cytosolic protein were respectively extracted, and separated by. Two-dimensional gel electrophoresis and stained by colloidal Coomassie brilliant blue method. The gels were scanned with Lab Scan III system and analyzed by Imagemaster software 6.0. The determinant criterion of differential protein was statistical significance of the volume% of the same protein spot between the two groups of various time points (i.e. P value was less than 0.05 which obtained by t-test of heterogeneity of variance and then adjusted by false discovery rate (FDR)), and difference of volume% exceeding twofold compared with NC group. The differentially expressed proteins were subject to MALDI-TOF-MS and Mascot search engine analysis to get the molecular weight and pI value of the protein. Gene Ontology (GO) classification and over expression analysis of the differential proteins were conducted using GoMinerTM and BIGO software. Homology and conservation of phosphorylations sites of Ephx2 were further analyzed.
2. Dynamic proteomic analysis of high glucose cultured rat glomerular mesangial cells.
Primary glomerular mesangial cells of the 5th generation were cultured. Cells were cultured in 5.4 mM normal glucose (NG) and 30 mM high glucose (HG) for 0,8,16,72 hour and 25 day respectively. Cell total protein of both groups at different time point were extracted and separated by two-dimensional gel electrophoresis. The differential proteins were analyzed and identified by the same methods mentioned above. Protein interaction network were imported from IntAct Web Service Client, illustrated by cytoscape and analyzed by MCODE.
Results:
1. Compared with LETO rats:in the cytosolic fractions,9 protein spots (identified as Gapdh, Qdpr, Fah, similar to Protein C14orf159 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl) were down-regulated, and 8 (identified as Gapdh, Qdpr, Fah, similar to Protein C14orfl59 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl) were up-regulated (identified as Qdpr, Ephx2, Fthfd, Tf, Naprtl, Idh1, Fah, Cryab); In the membrane fractions,11 protein spots (identified as Uqcrfs1, Nrn11, Pbld, LOC683519, Calb1, Acadsb, Dmgdh, Etfb) were down-regulated and 10 (LOC683519, Qdpr, GMPK, Etfb, Uqcrfsl, Fah, Dmgdh, Gpx3, cytokeratin 8 polypeptide) up-regulated. The differential expressed proteins of OLETF and LETO rats were mainly located in the cytosol, mitochondria and cyto plasmic vesicle. Their molecular functions were mainly related to ion, vitamin and protein transportation, with the biological functions of oxidation-reduction reaction, electron carrier, transporter and antioxidant, and were primarily involved in cell communication, cell apoptosis, response to stress and cell metabolic process such as aromatic compound, oxygen and reactive oxygen species. GO analysis verified biology process related to those proteins were oxidation reduction, aromatic compound metabolic process, carboxylic acid metabolic process, oxygen and reactive oxygen species metabolic process, acute inflammatory response, fatty acid metabolic process, monocarboxylic acid metabolic process. MALDI-TOF-MS results suggested Qdpr、Ephx2、LOC683519、GMPK in different spots stand for different phosphorylation states. Homology of ephx2 was high, and Thr-50、Thr-59、Ser-70 of ephx2 were much conserved in rat, mouse and human.
2.28 differential protein spots were found between NC and HG group. Among those in 8, 16h,2 (Rcn2, Hspb1) up regulated, and 24 (Tcpl, Wdrl, Cct2, Enol, Adss, Eeflg, Idhl, Pcbpl, Akrlbl, rCG53488, Pgaml, Psma6, Psmb7, Prdx6, Gstpl, Stmn1, Sodl, Krt2-7, Hmgb1, Serpinb9) were down regulated. In 72 h,2 (Psma6, Hmgbl) were down regulated. At the 25th day of culture,2 were up regulated (Pdia3 and Idh3a) over twofold. The differentially expressed proteins were mainly located in the cytosol, nucleus, cytoskeleton, mitochondria and endoplasmic reticulum. They could be bound with proteins, nucleic acids, ions. Their molecular function were related with antioxidant, oxidation-reduction, hydrolytic enzyme and isomerase, were primarily involved in the biological process such as cell communication, cell cycle, apoptosis, proliferation and metabolic process of carbohydrate, DNA, RNA, protein, oxygen and active oxygen. Gene ontology(GO) over expression and protein interaction analysis revealed that those protein were not only linked with already known diabetic nephropathy process such as glucose metabolism, oxidative stress and molecular chaperones, but also related to protein degradation.
Conclusions:
1.Some of differentially expressed proteins or their modification transform like Qdpr、Ephx2、Fah、Fthfd and p55 protein, which found in OLETF, were newly linked with pathogenesis of type 2 diabetic nephropathy. It can be concluded that type2 DN is not only associated with protein abundance changes but also modification changes. Especially we found ephx2 which perform important function in body, can be phosphorylated and its phosphorylation is changed in DN seems much more prospective. Those found would provide new clues about the etiopathogenisis of diabetic nephropathy.
2.PCBP1, HMGB1, Psma6, Psmb7, Prdx6, Rcn2 and Serpinb9 are newly found to be dynamically changed in the mesangial cells response to high glucose conditions. Through bioinformatics analysis, we found Proteasomes dysfunction might play an important role in proliferation and hypertrophy of mesangial cells in response to high glucose conditions which might provide new clues of the pathogenesis of diabetic nephropathy.
糖尿病肾病(Diabetic nephropathy, DN)是糖尿病常见的微血管并发症,它不仅是慢性肾功能衰竭患者肾移植的主要原因,还能大幅增加糖尿病患者心血管疾病的死亡率。肾小球硬化是1型与2型DN共同的特征性肾脏病理改变。DN发病机制非常复杂,涉及氧化应激、多元醇通路激活、糖基化终末产物沉积、血流动力学改变及诸多细胞因子异常等因素,为了深入揭示DN肾小球硬化的病理机制,本研究采用蛋白质组学技术,以体内与体外实验相结合,通过自发型2型DN模型OLETF大鼠肾皮质胞浆和胞膜亚差异蛋白质组学研究和高糖环境下大鼠肾小球系膜细胞动态差异蛋白质组学研究,探讨DN时肾小球硬化发病过程中蛋白质组学变化规律,以期更加深入理解DN肾小球硬化的发生机理。
方法：
1.自发型2型DN模型OLETF大鼠差异蛋白质组学研究
OLETF大鼠和遗传背景相似但不发病的LETO大鼠各7只用于本实验。实验中OLETF大鼠血糖及尿蛋白排泄呈渐进性升高,出现肾小球硬化及间质纤维化等类似于人类2型DN的肾脏病理改变。动物在36周龄时处死取材,分离肾皮质,分别提取胞浆和胞膜总蛋白。获得的蛋白样品经双向电泳分离,胶体考马斯亮蓝染色显示。扫描输入计算机,用图像分析软件ImageMaster 6.0对凝胶进行分析,差异蛋白判定标准为：该蛋白点在LETO和OLETF两组间有统计学差异(两组蛋白点的volume%先经方差不齐t检验获得p,后经FDR校正后p<0.05),且volume%值变化超过2倍。将凝胶中的差异蛋白点切出,经胶内胰蛋白酶解和MALDI-TOF-MS获得肽质量指纹谱并进行Mascot对蛋白质进行分析。利用GoMinerTM、BINGO软件对差异蛋白质进行Gene Ontology(GO)分类和过度表达分析。对发现磷酸修饰的蛋白进行进一步的同源性和磷酸化位点保守性分析。
2.高糖环境下大鼠肾小球系膜细胞动态差异蛋白质组学研究
原代分离培养并传至第5代的大鼠肾小球系膜细胞分别置含5.5mM(正常对照组,NC组)和30mM葡萄糖(高糖组,HG组)培养基中,分别培养0h、8h、16h、72h、25day,提取细胞总蛋白。蛋白样品经双向电泳技术分离,胶体考马斯亮蓝显示,差异蛋白分析、判定,利用MALDI-TOF-MS获得肽指纹图谱进行蛋白鉴定,对凝胶上多个蛋白点代表同一种蛋白质的肽指纹图谱进行磷酸化修饰分析,对差异蛋白进行GO功能分类及过度表达分析。从IntAct Web Service Clien获取差异蛋白质的相互作用网路,用Cytoscape显示,并用MCODE分析。
结果：
1.描述了36周龄OLETF和LETO大鼠肾皮质胞浆和胞膜蛋白的差异蛋白质组学变化。与LETO大鼠相比OLETF大鼠肾皮质胞浆蛋白中9个蛋白点(Gapdh, Qdpr, Fah, similar to Protein C14orf159 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl)下调,8个蛋白点(Qdpr, Ephx2, Fthfd, Tf, Naprtl, Idh1, Fah, Cryab)上调。胞膜蛋白中11个蛋白点(Uqcrfsl, Nrnll, Pbld, LOC683519, Calbl, Acadsb, Dmgdh, Etfb)下调,10个蛋白点(LOC683519, Qdpr, GMPK, Etfb, Uqcrfsl, Fah, Dmgdh, Gpx3, cytokeratin 8 polypeptide)上调。这些差异蛋白主要定位在胞浆、线粒体和细胞小泡。能够和离子、维生素、蛋白结合,其分子功能主要和氧化还原活性、电子传递、转运、抗氧化有关,主要参与细胞信号传导、细胞凋亡、应激反应和芳香族氨基酸、氧和活性氧代谢过程。其参与的生物学过程包括氧化还原、羧酸代谢、一元羧酸代谢、急性炎症反应、应激反应、脂肪酸代谢过度表达等。研究中发现多个不同的点代表相同的蛋白质,提示不同的转录版本或不同的翻译后修饰在DN发病过程中有重要作用。初步判断Qdpr, Ephx2、LOC683519、GMPK在DN发病过程中发生了磷酸化修饰的改变。Ephx2同源性较高,Thr-50、Thr-59、Ser-70在人、小鼠、大鼠中保守性较高。
2.描述了高糖环境对肾小球系膜细胞影响的蛋白质组学动态变化。细胞蛋白质组学结果分析发现28个差异蛋白点,其中在8h和16h2个蛋白点表达上调(Rcn2, Hspb1),24个蛋白点(Tcpl, Wdrl, Cct2, Eno1, Adss, Eef1g, Idhl, Pcbpl, Akrlbl, rCG53488, Pgam1, Psma6, Psmb7, Prdx6, Gstpl, Stmn1, Sodl, Krt2-7, Hmgb1, Serpinb9)表达下调,72小时2个蛋白点(Psma6, Hmgbl)表达下调,25天有2个蛋白点(Pdia3, Idh3a)表达上调。差异表达的蛋白主要定位在胞浆、胞核、细胞骨架、线粒体和内质网上,能与蛋白、核酸、离子结合,其分子功能以抗氧化活性、氧化还原活性、水解酶活性、异构酶活性为主；并参与细胞信号、细胞周期、凋亡、细胞增殖、细胞碳水化合物代谢、DNA代谢、RNA代谢、蛋白质代谢、氧和活性氧代谢等多种生物过程。GO过度表达和蛋白相互作用分析发现差异蛋白不仅和已知在DN发病中起到重要作用的糖代谢、氧化应激、分子伴侣有关,还和蛋白酶体相关的蛋白降解过程密切相关。
结论：
1.本研究结果发现与基因背景类似的正常LETO大鼠相比糖尿病肾病大鼠OLETF大鼠中Qdpr、Ephx2、Fah、Fthfd、p55 protein等蛋白表达丰度或磷酸化修饰的改变,尤其是发现体内有着重要功能的Ephx2存在磷酸化修饰,且在糖尿病肾病下发生了磷酸化修饰的改变。提示在DN肾小球硬化过程中,许多蛋白不仅存在丰度变化,还存在转录后修饰变化。这些发现为DN肾小球硬化机理研究提供新的思路。
2.本研究结果发现高糖环境下系膜细胞PCBP1、HMGB1、Psma6、Psmb7、Prdx6、Rcn2、Serpinb9等蛋白表达丰度发生了动态改变。通过信息生物学研究发现除了已知的通路外,蛋白酶体通路也发生了改变,提示该通路与高糖环境下的肾小球系膜细胞增殖、肥大有着重要作用。这些发现可能为DN肾小球硬化机制研究提供新的思路。
Objective:Diabetic nephropathy is the leading cause of end stage renal disease, and is associated with increased cardiovascular mortality. The major renal pathological changes of diabetic nephropathy both developed from type 1 and type 2 diabetes are glomerular sclerosis. The major mechanism of diabetic nephropathy is not clear up to now, although oxidative stress, polyol pathway activation, advanced glycation end products, hemodynamics and various cytokines are presumed to be the main culprits of development of diabetic nephropathy. To explore the pathophysiologic mechanisms of diabetic nephropathy in depth, and improve our understanding of DN pathogenesis, proteomics strategy was performed to screen for dynamic proteomics profile of mesangial cells in response to high glucose condition and global changes of renal cortex protein expression in OLETF and LETO rats.
Methods:
1. Differential proteomics study of spontaneous type 2 diabetes model of OLETF and LETO rats.
Spontaneous diabetic rat of OLETF and healthy control rats with the same genetic background LETO rats were used in this experiment. OLETF rats developed hyperglycemia, progressive increase of urinary protein excretion and glomeruloscerosis. OLETF and LETO rats were sacrificed at the age of 36 weeks, and the renal cortical total membrane and cytosolic protein were respectively extracted, and separated by. Two-dimensional gel electrophoresis and stained by colloidal Coomassie brilliant blue method. The gels were scanned with Lab Scan III system and analyzed by Imagemaster software 6.0. The determinant criterion of differential protein was statistical significance of the volume% of the same protein spot between the two groups of various time points (i.e. P value was less than 0.05 which obtained by t-test of heterogeneity of variance and then adjusted by false discovery rate (FDR)), and difference of volume% exceeding twofold compared with NC group. The differentially expressed proteins were subject to MALDI-TOF-MS and Mascot search engine analysis to get the molecular weight and pI value of the protein. Gene Ontology (GO) classification and over expression analysis of the differential proteins were conducted using GoMinerTM and BIGO software. Homology and conservation of phosphorylations sites of Ephx2 were further analyzed.
2. Dynamic proteomic analysis of high glucose cultured rat glomerular mesangial cells.
Primary glomerular mesangial cells of the 5th generation were cultured. Cells were cultured in 5.4 mM normal glucose (NG) and 30 mM high glucose (HG) for 0,8,16,72 hour and 25 day respectively. Cell total protein of both groups at different time point were extracted and separated by two-dimensional gel electrophoresis. The differential proteins were analyzed and identified by the same methods mentioned above. Protein interaction network were imported from IntAct Web Service Client, illustrated by cytoscape and analyzed by MCODE.
Results:
1. Compared with LETO rats:in the cytosolic fractions,9 protein spots (identified as Gapdh, Qdpr, Fah, similar to Protein C14orf159 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl) were down-regulated, and 8 (identified as Gapdh, Qdpr, Fah, similar to Protein C14orfl59 mitochondrial precursor, Ephx2, Alb, Acadsb, Clybl) were up-regulated (identified as Qdpr, Ephx2, Fthfd, Tf, Naprtl, Idh1, Fah, Cryab); In the membrane fractions,11 protein spots (identified as Uqcrfs1, Nrn11, Pbld, LOC683519, Calb1, Acadsb, Dmgdh, Etfb) were down-regulated and 10 (LOC683519, Qdpr, GMPK, Etfb, Uqcrfsl, Fah, Dmgdh, Gpx3, cytokeratin 8 polypeptide) up-regulated. The differential expressed proteins of OLETF and LETO rats were mainly located in the cytosol, mitochondria and cyto plasmic vesicle. Their molecular functions were mainly related to ion, vitamin and protein transportation, with the biological functions of oxidation-reduction reaction, electron carrier, transporter and antioxidant, and were primarily involved in cell communication, cell apoptosis, response to stress and cell metabolic process such as aromatic compound, oxygen and reactive oxygen species. GO analysis verified biology process related to those proteins were oxidation reduction, aromatic compound metabolic process, carboxylic acid metabolic process, oxygen and reactive oxygen species metabolic process, acute inflammatory response, fatty acid metabolic process, monocarboxylic acid metabolic process. MALDI-TOF-MS results suggested Qdpr、Ephx2、LOC683519、GMPK in different spots stand for different phosphorylation states. Homology of ephx2 was high, and Thr-50、Thr-59、Ser-70 of ephx2 were much conserved in rat, mouse and human.
2.28 differential protein spots were found between NC and HG group. Among those in 8, 16h,2 (Rcn2, Hspb1) up regulated, and 24 (Tcpl, Wdrl, Cct2, Enol, Adss, Eeflg, Idhl, Pcbpl, Akrlbl, rCG53488, Pgaml, Psma6, Psmb7, Prdx6, Gstpl, Stmn1, Sodl, Krt2-7, Hmgb1, Serpinb9) were down regulated. In 72 h,2 (Psma6, Hmgbl) were down regulated. At the 25th day of culture,2 were up regulated (Pdia3 and Idh3a) over twofold. The differentially expressed proteins were mainly located in the cytosol, nucleus, cytoskeleton, mitochondria and endoplasmic reticulum. They could be bound with proteins, nucleic acids, ions. Their molecular function were related with antioxidant, oxidation-reduction, hydrolytic enzyme and isomerase, were primarily involved in the biological process such as cell communication, cell cycle, apoptosis, proliferation and metabolic process of carbohydrate, DNA, RNA, protein, oxygen and active oxygen. Gene ontology(GO) over expression and protein interaction analysis revealed that those protein were not only linked with already known diabetic nephropathy process such as glucose metabolism, oxidative stress and molecular chaperones, but also related to protein degradation.
Conclusions:
1.Some of differentially expressed proteins or their modification transform like Qdpr、Ephx2、Fah、Fthfd and p55 protein, which found in OLETF, were newly linked with pathogenesis of type 2 diabetic nephropathy. It can be concluded that type2 DN is not only associated with protein abundance changes but also modification changes. Especially we found ephx2 which perform important function in body, can be phosphorylated and its phosphorylation is changed in DN seems much more prospective. Those found would provide new clues about the etiopathogenisis of diabetic nephropathy.
2.PCBP1, HMGB1, Psma6, Psmb7, Prdx6, Rcn2 and Serpinb9 are newly found to be dynamically changed in the mesangial cells response to high glucose conditions. Through bioinformatics analysis, we found Proteasomes dysfunction might play an important role in proliferation and hypertrophy of mesangial cells in response to high glucose conditions which might provide new clues of the pathogenesis of diabetic nephropathy.
引文
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