Drp-1基因参与高糖诱导胰岛β细胞凋亡的相关机制研究
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摘要
β细胞功能衰竭是2型糖尿病晚期一个重要的特征，高糖诱导的细胞凋亡是胰岛β细胞功能衰竭一个重要原因。深入研究高糖诱导胰岛β细胞凋亡的分子机制对阐明2型糖尿病的发生和发展机制以及对糖尿病的防治都具有重要的意义。
线粒体分裂蛋白(Dynamin-related protein 1, Drp-1)是参与线粒体分裂的主要分子，凋亡早期线粒体出现明显的分裂过程增强，高糖可上调Drp-1基因的表达，但Drp-1基因表达与高糖诱导的胰岛β细胞凋亡的关系尚未见报道。
目的：研究线粒体分裂蛋白(Dynamin-related protein 1, Drp-1)的表达对高糖诱导胰岛β细胞凋亡的影响，探讨线粒体分裂与β细胞凋亡的分子机制。
方法：
1)构建Drp-1和Drp-1K38A质粒，．应用基因转染技术在大鼠胰岛β细胞(INS-1)构建表达Drp-1野生型(Drp-1WT)和Drp-1突变型(Drp-1K38A)基因的可诱导细胞系，并用细胞免疫荧光和实时定量PCR(Real-time polymerase chain reaction,Real-time PCR)方法证实转染基因的可诱导性．，采用免疫蛋白印迹(Western blot)分析Doxycycline(Dox)诱导后胰岛β细胞Drp-1表达的时-效关系和量-效关系，确定Dox的最佳作用剂量和作用时间。
2)分析高糖条件下Drp-1基因的表达，．以及Drp-1的表达对胰岛β细胞增殖的影响；Real-time PCR和酶联免疫吸附试验(enzyme linked immunosorbentassy,ELISA)分析Drp-1表达对胰岛素mRNA的表达和胰岛素释放的影响。应用生物化学的方法分析Drp-1表达对胰岛β细胞能量代谢的影响。应用AnnexinⅤ-PI、Hochest33342-PI、TUNEL染色及DNA Ladder分析在高糖条件，．Dox诱导前后胰岛β细胞凋亡的情况。
3)应用免疫蛋白印迹(Western blot)方法比较不同糖浓度时，Dox诱导前后Drp-1的表达和细胞色素c的释放相关性。应用微孔板式连续荧光光谱仪测定不同条件下细胞内凋亡蛋白酶Caspase3的活性。应用透射电子显微镜和激光共聚焦显微镜观察Dox诱导前后线粒体的形态变化并在共聚焦显微镜下分析细胞色素c在细胞内的分布。应用流式细胞术比较Dox诱导前后细胞线粒体膜电位的变化和细胞内活性氧(Reactive oxygen species, ROS)的产生。
结果：
1)Drp-1可诱导细胞系的鉴定：免疫荧光和Western blot的结果显示，Dox诱导后Drp-1基因表达在野生型(Drp-1WT)和突变型(Drp-1K38A)细胞系表达明显增加，并且Drp-1的表达与Dox之间存在明显的剂量—依赖和时间—依赖关系，500ng／ml Dox诱导24h后，Drp-1的表达即明显增加，96h达高峰。
2)Drp-1表达对胰岛β细胞功能的影响：MTT结果显示：Dox诱导后，细胞增殖和胰岛素分泌能力在Drp-1WT细胞明显降低，而在Drp-1K38A细胞变化不大，这种现象在高糖培养条件时更明显。能量代谢的实验结果显示：在高糖条件下，Drp-1WT细胞在Dox诱导后的呼吸酶复合体活性明显升高，ATP含量减少。凋亡的分析结果表明：在高糖条件下，经Dox诱导后Drp-1WT细胞的凋亡明显多于Drp-1K38A细胞。
3)Drp-1表达参与胰岛β细胞凋亡的机制：透射电镜和激光共聚焦显微镜观察发现：在高糖条件下，Dox诱导后的Drp-1WT细胞中的可见线粒体分裂和细胞色素c的释放。生物学分析结果表明：细胞中的线粒体膜电位降低、caspase3活性升高、ROS产生增加，而这些变化在Drp-1K38A细胞变化不明显。
结论：Drp-1基因表达参与高糖诱导的胰岛β细胞凋亡。
The beta cell dysfunction is an important characteristic of the late stage ofType 2 diabetes. High glucose induced-beta cell apoptosis played a crucial role in theprocess of beta cell dysfunction. It is important for understanding the pathogenesisof type 2 diabetes development and for its prevention and treatment to furtherinvestigate the molecular mechanism of high glucose-induced isletβcell apoptosis.
Dynamin-related protein1 (Drp-1) was a main factor in mitochondrial fission.Mitochondria underwent rapid, extensive fragmentation early in the apoptotic process.Drp-1 gene expression was up-regulated by high glucose. But the relation betweenexpression of Drp-1 gene and high glucose inducedβcell apoptosis was not wellunderstood.
Objectives: To explore the effect of Dynamin-related protein 1(Drp-1) geneoverexpression on high glucose induced beta-cell dysfunction.
Methods: The inducible wild-type Drp-1(Drp-1WT) and dominant-negative mutant ofDrp-1(Drp-1K38A) stable cell lines were respectively established using Tet-on Systemin INS-1 cells. The expression of Drp-1 induced by doxycycline in the both cell lineswas confirmed by immunofluorescence staining and western blot. The cell viability andinsulin secretion were analyzed when the both cell lines were cultured in standard orhigh glucose conditions with or without doxycycline. The activities of the fourcomplexes of the respiratory chain were assayed using biochemical methods.Theproduction of ATP in Drp-1WT and Drp-1K38A cells was estimated usingbioluminescent methods.The doxycycline induced cell apoptosis was detected byAnnexinⅤ-PI, Hochest33342-PI、TUNEL staining and DNA fragmentation, respectively. The mitochondrial morphology and membrane potential, the release ofcytochrome C, Caspase-3 activity and the reactive oxygen species (ROS) generationwere further investigated for understanding the relevant mechanisms of the cellapoptosis.
Results: Drp-1 expression was significantly induced in the both inducible cell lines inresponse to doxycycline. After induction of doxycycline, the cell viability and insulinsecretion were reduced in Drp-1WT cells, but not in Drp-1K38A cells, especially inhigh glucose condition. It was found that the activities of the four complexes of therespiratory chain in the mitochondria of Drp-1WT cells and Drp-1K38A cells werealmost no change after Dox induction in standard glucose or high glucose condition.But the production of ATP in the mitochondria of Drp-1WT cells in high glucosecondition was decreased after Dox induction. The doxycycline induced cell apoptosiswas more in Drp-1WT cells and was less in Drp-1K38A cells in high glucose condition.Furthermore, the mitochondrial fission and the release of cytochrome C were observedin Drp-1WT cells by electron microscopy and confocal microscopy. The mitochondriamembrane potential was decreased and Caspase-3 activity and ROS generation weresignificantly increased in Drp-1WT cells, but were less in Drp-1K38A cells.
Conclusions: Drp-1 expression may participate in high glucose induced beta celldysfunction.
线粒体分裂蛋白(Dynamin-related protein 1, Drp-1)是参与线粒体分裂的主要分子，凋亡早期线粒体出现明显的分裂过程增强，高糖可上调Drp-1基因的表达，但Drp-1基因表达与高糖诱导的胰岛β细胞凋亡的关系尚未见报道。
目的：研究线粒体分裂蛋白(Dynamin-related protein 1, Drp-1)的表达对高糖诱导胰岛β细胞凋亡的影响，探讨线粒体分裂与β细胞凋亡的分子机制。
方法：
1)构建Drp-1和Drp-1K38A质粒，．应用基因转染技术在大鼠胰岛β细胞(INS-1)构建表达Drp-1野生型(Drp-1WT)和Drp-1突变型(Drp-1K38A)基因的可诱导细胞系，并用细胞免疫荧光和实时定量PCR(Real-time polymerase chain reaction,Real-time PCR)方法证实转染基因的可诱导性．，采用免疫蛋白印迹(Western blot)分析Doxycycline(Dox)诱导后胰岛β细胞Drp-1表达的时-效关系和量-效关系，确定Dox的最佳作用剂量和作用时间。
2)分析高糖条件下Drp-1基因的表达，．以及Drp-1的表达对胰岛β细胞增殖的影响；Real-time PCR和酶联免疫吸附试验(enzyme linked immunosorbentassy,ELISA)分析Drp-1表达对胰岛素mRNA的表达和胰岛素释放的影响。应用生物化学的方法分析Drp-1表达对胰岛β细胞能量代谢的影响。应用AnnexinⅤ-PI、Hochest33342-PI、TUNEL染色及DNA Ladder分析在高糖条件，．Dox诱导前后胰岛β细胞凋亡的情况。
3)应用免疫蛋白印迹(Western blot)方法比较不同糖浓度时，Dox诱导前后Drp-1的表达和细胞色素c的释放相关性。应用微孔板式连续荧光光谱仪测定不同条件下细胞内凋亡蛋白酶Caspase3的活性。应用透射电子显微镜和激光共聚焦显微镜观察Dox诱导前后线粒体的形态变化并在共聚焦显微镜下分析细胞色素c在细胞内的分布。应用流式细胞术比较Dox诱导前后细胞线粒体膜电位的变化和细胞内活性氧(Reactive oxygen species, ROS)的产生。
结果：
1)Drp-1可诱导细胞系的鉴定：免疫荧光和Western blot的结果显示，Dox诱导后Drp-1基因表达在野生型(Drp-1WT)和突变型(Drp-1K38A)细胞系表达明显增加，并且Drp-1的表达与Dox之间存在明显的剂量—依赖和时间—依赖关系，500ng／ml Dox诱导24h后，Drp-1的表达即明显增加，96h达高峰。
2)Drp-1表达对胰岛β细胞功能的影响：MTT结果显示：Dox诱导后，细胞增殖和胰岛素分泌能力在Drp-1WT细胞明显降低，而在Drp-1K38A细胞变化不大，这种现象在高糖培养条件时更明显。能量代谢的实验结果显示：在高糖条件下，Drp-1WT细胞在Dox诱导后的呼吸酶复合体活性明显升高，ATP含量减少。凋亡的分析结果表明：在高糖条件下，经Dox诱导后Drp-1WT细胞的凋亡明显多于Drp-1K38A细胞。
3)Drp-1表达参与胰岛β细胞凋亡的机制：透射电镜和激光共聚焦显微镜观察发现：在高糖条件下，Dox诱导后的Drp-1WT细胞中的可见线粒体分裂和细胞色素c的释放。生物学分析结果表明：细胞中的线粒体膜电位降低、caspase3活性升高、ROS产生增加，而这些变化在Drp-1K38A细胞变化不明显。
结论：Drp-1基因表达参与高糖诱导的胰岛β细胞凋亡。
The beta cell dysfunction is an important characteristic of the late stage ofType 2 diabetes. High glucose induced-beta cell apoptosis played a crucial role in theprocess of beta cell dysfunction. It is important for understanding the pathogenesisof type 2 diabetes development and for its prevention and treatment to furtherinvestigate the molecular mechanism of high glucose-induced isletβcell apoptosis.
Dynamin-related protein1 (Drp-1) was a main factor in mitochondrial fission.Mitochondria underwent rapid, extensive fragmentation early in the apoptotic process.Drp-1 gene expression was up-regulated by high glucose. But the relation betweenexpression of Drp-1 gene and high glucose inducedβcell apoptosis was not wellunderstood.
Objectives: To explore the effect of Dynamin-related protein 1(Drp-1) geneoverexpression on high glucose induced beta-cell dysfunction.
Methods: The inducible wild-type Drp-1(Drp-1WT) and dominant-negative mutant ofDrp-1(Drp-1K38A) stable cell lines were respectively established using Tet-on Systemin INS-1 cells. The expression of Drp-1 induced by doxycycline in the both cell lineswas confirmed by immunofluorescence staining and western blot. The cell viability andinsulin secretion were analyzed when the both cell lines were cultured in standard orhigh glucose conditions with or without doxycycline. The activities of the fourcomplexes of the respiratory chain were assayed using biochemical methods.Theproduction of ATP in Drp-1WT and Drp-1K38A cells was estimated usingbioluminescent methods.The doxycycline induced cell apoptosis was detected byAnnexinⅤ-PI, Hochest33342-PI、TUNEL staining and DNA fragmentation, respectively. The mitochondrial morphology and membrane potential, the release ofcytochrome C, Caspase-3 activity and the reactive oxygen species (ROS) generationwere further investigated for understanding the relevant mechanisms of the cellapoptosis.
Results: Drp-1 expression was significantly induced in the both inducible cell lines inresponse to doxycycline. After induction of doxycycline, the cell viability and insulinsecretion were reduced in Drp-1WT cells, but not in Drp-1K38A cells, especially inhigh glucose condition. It was found that the activities of the four complexes of therespiratory chain in the mitochondria of Drp-1WT cells and Drp-1K38A cells werealmost no change after Dox induction in standard glucose or high glucose condition.But the production of ATP in the mitochondria of Drp-1WT cells in high glucosecondition was decreased after Dox induction. The doxycycline induced cell apoptosiswas more in Drp-1WT cells and was less in Drp-1K38A cells in high glucose condition.Furthermore, the mitochondrial fission and the release of cytochrome C were observedin Drp-1WT cells by electron microscopy and confocal microscopy. The mitochondriamembrane potential was decreased and Caspase-3 activity and ROS generation weresignificantly increased in Drp-1WT cells, but were less in Drp-1K38A cells.
Conclusions: Drp-1 expression may participate in high glucose induced beta celldysfunction.
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