氧化应激和JNK信号途径介导的INS-1细胞高糖毒性作用机制研究
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摘要
葡萄糖是生理条件下调节胰岛β细胞功能的重要营养物质。机体存在一定数量功能正常的β细胞是维持糖稳态的基础。胰岛β细胞功能减退导致葡萄糖代谢异常,促进糖尿病发生。显著的高血糖通过糖毒性作用进一步损害β细胞功能是加速糖尿病病情进展的病理生理机制。氧化应激是指体内的活性氧(ROS)生成增加和(或)清除活性氧的能力降低,导致活性氧生成和清除失衡,机体内过量的活性氧聚集导致组织、细胞功能受损。2型糖尿病患者因为高血糖、高血脂导致机体氧化应激反应发生,过量的能量物质代谢同时加重胰腺组织内的氧化应激反应,导致活性氧产生增加。在胰岛细胞内活性氧的产生与血糖的关系如何,高血糖是否通过胞内活性氧损害了β细胞功能,氧化应激是否参与形成糖毒性的机制是本课题研究的内容之一。
机体内的各种信号系统通过相互作用调节细胞功能。胰岛素信号系统主要在胰岛素靶器官表达,具有调节胰岛β细胞功能和外周组织胰岛素敏感性的重要地位。β细胞上的胰岛素受体信号系统受损导致β细胞功能损害。JNK信号分子属于应激激活蛋白激酶家族中的成员,在机体受到创伤、炎症反应、放射线照射时被激活,通过活化其下游底物主要调节细胞的生长与存活。β细胞内存在JNK信号分子的表达,本研究通过观察高糖环境是否激活β细胞内的JNK信号通路以及JNK信号通路与胰岛素受体信号系统是否相互作用介导糖毒性的产生,从而为有效地减轻糖毒性,保护β细胞功能提供有价值的干预分子靶点。
一、不同葡萄糖浓度下培养INS-1细胞,检测细胞的活性与凋亡、基因转录功能
1、观察不同浓度的葡萄糖作用不同时间对β细胞系INS-1细胞活性和凋亡的影响:
在5.6mmol/l(5.6G)、11.2 mmol/l(11.2G)、33.3 mmol/l(33.3G)葡萄糖浓度下培养INS-1细胞48、72小时, MTT方法检测细胞活性,免疫荧光Hoechst染色和Annexin V-FITC/PI双标记流式细胞术检测细胞凋亡。RT-PCR方法检测细胞胰岛素、PDX-1、IAPP的mRNA转录水平,加入IGF-1以后检测细胞活性和基因转录水平改变。
2、高糖随时间增加对INS-1细胞功能损伤程度加重:
MTT活性检测显示一定范围内的葡萄糖浓度增加促进细胞活性;随葡萄糖浓度进一步增加,细胞活性受抑制;72小时,33.3mmol/l葡萄糖浓度下,细胞活性抑制达17.7%(p<0.001);Hoechst染色显示培养72小时只有33.3G组INS-1细胞有明显凋亡;流式细胞术检测培养细胞72小时后33.3G组凋亡细胞比例为28.2%,是基础对照组的2.49倍(P<0.001)。随葡萄糖浓度和培养时间增加,INS-1细胞的胰岛素、PDX-1基因转录受抑制程度逐渐增加;加入细胞因子IGF-1以后可以改善细胞活性、增加胰岛素和PDX-1的转录水平,但随葡萄糖浓度增加,其促进生长的作用减弱;培养48小时,11.2mmol/l、33.3mmol/l葡萄糖抑制IAPP的基因转录;长期高糖培养(72小时),IAPP基因转录增强。IGF-1抑制IAPP的基因转录。
二、检测不同浓度葡萄糖培养下INS-1细胞内活性氧(ROS)的水平,以及给与活性氧清除剂NAC以后,细胞功能的改变。
1、胞内活性氧随葡萄糖浓度增加而增加:
培养48小时,11.2G和33.3G组胞内ROS较对照组分别上升15%和32%(,P<0.001)。培养至72小时,11.2G组和33.3G组胞内ROS较对照组分别增加25.3%和49.6%(P<0.001),给与NAC显著降低不同糖浓度下的胞内活性氧水平。
2、活性氧清除剂NAC改善高糖环境中的INS-1细胞功能:
加入NAC有效地改善了高糖环境中的INS-1细胞活性, 48小时和72小时,33.3G组细胞活性较干预前分别增加28%和20%( P<0.01);细胞凋亡减少54%(P<0.001);胰岛素、PDX-1基因转录水平显著提高,48小时内可以完全逆转高糖环境中的胰岛素基因转录水平。
三、研究高糖损伤INS-1细胞功能的分子机制
1、阻断INK信号通路可以有效地改善INS-1细胞功能:给与JNK抑制剂SP600125以后, 48小时内有效改善高浓度葡萄糖对INS-1细胞活性的抑制作用,72小时33.3G组细胞凋亡减少45%(P<0.001),表明JNK的激活在糖毒性导致的β细胞凋亡中发挥了作用。此外高糖环境中的INS-1细胞胰岛素和PDX的基因转录水平也在阻断JNK通路后获得部分恢复。
2、高糖通过激活JNK信号通路进而抑制胰岛素信号系统可能是糖毒性损伤胰岛β细胞的分子机制之一
高糖环境激活INS-1细胞的JNK丝氨酸磷酸化,IGF-1抑制该位点的磷酸化过程。同时高糖培养可以激活IRS-ser-270磷酸化,33.3G组磷酸化水平是11.2G组的1.17倍(P<0.01)。加入JNK抑制剂SP600125以后,各葡萄糖组JNK磷酸化水平显著降低, 33.3G组JNK磷酸化蛋白被抑制90%;加入SP600125后11.2G组和33.3G组IRS-Ser-270的磷酸化水平只是部分被抑制,分别下降88.3%和80%;加入IGF-1进一步抑制IRS-Ser-270的丝氨酸水平。葡萄糖毒性部分通过激活JNK信号途径进而抑制INS-1细胞的胰岛素受体底物信号系统发挥作用。
结论(1)一定浓度范围内的葡萄糖促进INS-1细胞存活与生长。(2)慢性长期高糖环境抑制INS-1细胞的活性、促进细胞凋亡,损害其基因转录功能(。3)高糖诱发INS-1细胞发生胞内氧化应激,给与抗氧化应激干预显著抑制胞内氧化应激,并有效的改善细胞活性、减少细胞凋亡,促进胰岛素和PDX-1的基因转录。(4)高糖通过激活JNK磷酸化,进一步导致IRS-Ser-270磷酸化;阻断JNK信号通路,抑制其磷酸化过程进而部分抑制IRS-Ser-270的磷酸化,显著改善INS-1细胞功能(。5)高糖通过诱导INS-1细胞内的氧化应激,激活JNK诱导IRS的丝氨酸磷酸化,从而抑制胰岛素信号系统可能是高糖毒性的机制之一。
Glucose is the most original and major nutrition to regulate the function of theβ-cells in the physiologica condition. Normalβ-cells can compensate for insulin resistance by increasing insulin secretion orβ-cell mass to maintain the glucose homeostasis. Type 2 diabetes arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand, because of acquiredβ-cells secretory dysfunction and/or decreasedβ-cells mass. Once hyperglycemia becomes apparent, which can exert deleterious effects onβ-cell function gradually. This process is called“glucose toxicity”.
Oxidative stress can, therefore, be defined as the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. Experimental support for oxidative stress as a mediator of cell death and function impaired.Under diabetic conditions, reactive oxygen species(ROS) increase in various tissues due to the hyperglycemia and hyperlipemia which including pancteatic.Pancreaticβ-cells have recently emerged as a target of oxidative stress-mediated tissue damage.In our study we investigate the relationship of the ROS production and the glucose concentration in islet, how the ROS impaire the function ofβ-cells, whether it is involved in the glucose toxicity . Insulin receptor substrates signal are response for mediating intracellular signaling transduction to regulate the function ofβ-cells and the insulin sensitivity in liver, musle, adipose tissue. Abnormality of IRS signaling might explain the eventual loss of compensatory insulin secretory and contribute to failure ofβ-cells function. C-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli, and mediating cell growth and survive. The mechanisms whereby chronic elevations of glucose might damageβ-cells are our study will to investigate. We will explore whether that chronic oxidative stress and JNK pathway is involved in the mechanism that glucose excess can damageβ-cells and provides a target for that lessen glucose toxicity .
1. To investigate the effect of different concentration glucose on the function and apoptosis of INS-1 cells.
(1) Culturing the INS-1 cells at three glucose concentration: 5.6mmol/l, 11.2 mmol/l, 33.3 mmol/l, within 48 hours and 72 hours respectively. MTT used to measure cell viability, RT-PCT used to measure the insulin, PDX-1, IAPP gene expression of the INS-1 cells, apoptosis were examined by immuno- fluorescence and flow-cytometry analysis. After treating with IGF-1 measuring these items again.
(2) Expose INS-1 cells to elevated glucose concentrations lead to impaired cell function by time-dependent method.
We cultured the cells in 5.6mmol/l and 11.2 mmol/l glucose for 48h, the glucose dose not inhibit the cell viability and induce apoptosis.
There were remarkably increasing of the apoptise when INS-1 cells expose to 33.3mmol/l glucose, with a 2.49-fold increase to cells in the basal 5.6mmol/l glucose.In 11.2G a nd 33.3G group caused a 11.2% and 42.4% decrease of the insulin gene expression (P <0.001),also reduced the PDX-1 gene expression by 50% and 63%(p<0.001)After IGF-1 plus, insulin and PDX-1 mRNA level are increased, wherase the effctor were lessen with the elevated glucose.
2. Reactive oxygen species (ROS) were measured by enzyme linked immunosorbent assay.NAC added can improve the cells function in high glucose with decrease the ROS in the cells.
(1).The ROS production were increased with the elevated glucose concentration, longer the cells exposed to high concentration glucose, more the ROS production were. NAC decreased the ROS in any concentration of glucose.
(2).NAC treatment remarkably improve the function of INS-1 cells exposed to high glucose. NAC treatment led to cell viability increased and apoptosis cell decreased to 13% in 33.3G group. The mRNA level of insulin and PDX-1 were also increased after the INS-1 cell treated with NAC for 48h and 72h,for insulin were 41% and 77% increased(P<0.01) respectively,and for PDX-1 were 56% and 113%(P<0.01)increased respectively in 33.3G group.NAC treatment led to insulin and PDX-1 gene expression restoration nearly to the base level.
3. Western-blot methods to test the serine270 phosphorylation of IRS and phosphorylation of JNK inβcells, and investigate the mechanisms of glucose toxitity.
(1)SP600125 improves INS-1 cells function by inhibiting the JNK pathway. After SP600125 treatment caused a 45% decreased of the apoptosis cells in 33.3G group (P<0.01), and improveing the cytoactive. The mRNA level of insulin and PDX-1 were partly restored by inhibit the JNK signal pathway.
(2)High glucose lead to the the serine 270 phosphorylation of IRS correlates with JNK phosphorylation in INS-1 cells. Using Western-blot analysis, the levels of serine 270 phosphorylation of IRS were 1.17 fold increased in 33.3G JNK compares to 11.2G group(P<0.01). SP600125 treatment completely blocked the JNK phosphorylation, but partly blocked serine 270 phosphorylation of IRS.
Conclusion Chronic high glucose toxicity impair the INS-1 function and induce the cells developed apoptosis might be related to elevated glucose concentrations increase levels of reactive oxygen species in INS-1 cells. The antioxidant agent NAC protect INS-1 cells from glucose toxicity with the effect to improve the oxidative stress response in INS-1 cells.JNK pathway contribute to the glucose toxicity by inhibiting the IRS signal througe phosphorylate Ser270 of IRS in INS-1 cells.
机体内的各种信号系统通过相互作用调节细胞功能。胰岛素信号系统主要在胰岛素靶器官表达,具有调节胰岛β细胞功能和外周组织胰岛素敏感性的重要地位。β细胞上的胰岛素受体信号系统受损导致β细胞功能损害。JNK信号分子属于应激激活蛋白激酶家族中的成员,在机体受到创伤、炎症反应、放射线照射时被激活,通过活化其下游底物主要调节细胞的生长与存活。β细胞内存在JNK信号分子的表达,本研究通过观察高糖环境是否激活β细胞内的JNK信号通路以及JNK信号通路与胰岛素受体信号系统是否相互作用介导糖毒性的产生,从而为有效地减轻糖毒性,保护β细胞功能提供有价值的干预分子靶点。
一、不同葡萄糖浓度下培养INS-1细胞,检测细胞的活性与凋亡、基因转录功能
1、观察不同浓度的葡萄糖作用不同时间对β细胞系INS-1细胞活性和凋亡的影响:
在5.6mmol/l(5.6G)、11.2 mmol/l(11.2G)、33.3 mmol/l(33.3G)葡萄糖浓度下培养INS-1细胞48、72小时, MTT方法检测细胞活性,免疫荧光Hoechst染色和Annexin V-FITC/PI双标记流式细胞术检测细胞凋亡。RT-PCR方法检测细胞胰岛素、PDX-1、IAPP的mRNA转录水平,加入IGF-1以后检测细胞活性和基因转录水平改变。
2、高糖随时间增加对INS-1细胞功能损伤程度加重:
MTT活性检测显示一定范围内的葡萄糖浓度增加促进细胞活性;随葡萄糖浓度进一步增加,细胞活性受抑制;72小时,33.3mmol/l葡萄糖浓度下,细胞活性抑制达17.7%(p<0.001);Hoechst染色显示培养72小时只有33.3G组INS-1细胞有明显凋亡;流式细胞术检测培养细胞72小时后33.3G组凋亡细胞比例为28.2%,是基础对照组的2.49倍(P<0.001)。随葡萄糖浓度和培养时间增加,INS-1细胞的胰岛素、PDX-1基因转录受抑制程度逐渐增加;加入细胞因子IGF-1以后可以改善细胞活性、增加胰岛素和PDX-1的转录水平,但随葡萄糖浓度增加,其促进生长的作用减弱;培养48小时,11.2mmol/l、33.3mmol/l葡萄糖抑制IAPP的基因转录;长期高糖培养(72小时),IAPP基因转录增强。IGF-1抑制IAPP的基因转录。
二、检测不同浓度葡萄糖培养下INS-1细胞内活性氧(ROS)的水平,以及给与活性氧清除剂NAC以后,细胞功能的改变。
1、胞内活性氧随葡萄糖浓度增加而增加:
培养48小时,11.2G和33.3G组胞内ROS较对照组分别上升15%和32%(,P<0.001)。培养至72小时,11.2G组和33.3G组胞内ROS较对照组分别增加25.3%和49.6%(P<0.001),给与NAC显著降低不同糖浓度下的胞内活性氧水平。
2、活性氧清除剂NAC改善高糖环境中的INS-1细胞功能:
加入NAC有效地改善了高糖环境中的INS-1细胞活性, 48小时和72小时,33.3G组细胞活性较干预前分别增加28%和20%( P<0.01);细胞凋亡减少54%(P<0.001);胰岛素、PDX-1基因转录水平显著提高,48小时内可以完全逆转高糖环境中的胰岛素基因转录水平。
三、研究高糖损伤INS-1细胞功能的分子机制
1、阻断INK信号通路可以有效地改善INS-1细胞功能:给与JNK抑制剂SP600125以后, 48小时内有效改善高浓度葡萄糖对INS-1细胞活性的抑制作用,72小时33.3G组细胞凋亡减少45%(P<0.001),表明JNK的激活在糖毒性导致的β细胞凋亡中发挥了作用。此外高糖环境中的INS-1细胞胰岛素和PDX的基因转录水平也在阻断JNK通路后获得部分恢复。
2、高糖通过激活JNK信号通路进而抑制胰岛素信号系统可能是糖毒性损伤胰岛β细胞的分子机制之一
高糖环境激活INS-1细胞的JNK丝氨酸磷酸化,IGF-1抑制该位点的磷酸化过程。同时高糖培养可以激活IRS-ser-270磷酸化,33.3G组磷酸化水平是11.2G组的1.17倍(P<0.01)。加入JNK抑制剂SP600125以后,各葡萄糖组JNK磷酸化水平显著降低, 33.3G组JNK磷酸化蛋白被抑制90%;加入SP600125后11.2G组和33.3G组IRS-Ser-270的磷酸化水平只是部分被抑制,分别下降88.3%和80%;加入IGF-1进一步抑制IRS-Ser-270的丝氨酸水平。葡萄糖毒性部分通过激活JNK信号途径进而抑制INS-1细胞的胰岛素受体底物信号系统发挥作用。
结论(1)一定浓度范围内的葡萄糖促进INS-1细胞存活与生长。(2)慢性长期高糖环境抑制INS-1细胞的活性、促进细胞凋亡,损害其基因转录功能(。3)高糖诱发INS-1细胞发生胞内氧化应激,给与抗氧化应激干预显著抑制胞内氧化应激,并有效的改善细胞活性、减少细胞凋亡,促进胰岛素和PDX-1的基因转录。(4)高糖通过激活JNK磷酸化,进一步导致IRS-Ser-270磷酸化;阻断JNK信号通路,抑制其磷酸化过程进而部分抑制IRS-Ser-270的磷酸化,显著改善INS-1细胞功能(。5)高糖通过诱导INS-1细胞内的氧化应激,激活JNK诱导IRS的丝氨酸磷酸化,从而抑制胰岛素信号系统可能是高糖毒性的机制之一。
Glucose is the most original and major nutrition to regulate the function of theβ-cells in the physiologica condition. Normalβ-cells can compensate for insulin resistance by increasing insulin secretion orβ-cell mass to maintain the glucose homeostasis. Type 2 diabetes arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand, because of acquiredβ-cells secretory dysfunction and/or decreasedβ-cells mass. Once hyperglycemia becomes apparent, which can exert deleterious effects onβ-cell function gradually. This process is called“glucose toxicity”.
Oxidative stress can, therefore, be defined as the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. Experimental support for oxidative stress as a mediator of cell death and function impaired.Under diabetic conditions, reactive oxygen species(ROS) increase in various tissues due to the hyperglycemia and hyperlipemia which including pancteatic.Pancreaticβ-cells have recently emerged as a target of oxidative stress-mediated tissue damage.In our study we investigate the relationship of the ROS production and the glucose concentration in islet, how the ROS impaire the function ofβ-cells, whether it is involved in the glucose toxicity . Insulin receptor substrates signal are response for mediating intracellular signaling transduction to regulate the function ofβ-cells and the insulin sensitivity in liver, musle, adipose tissue. Abnormality of IRS signaling might explain the eventual loss of compensatory insulin secretory and contribute to failure ofβ-cells function. C-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli, and mediating cell growth and survive. The mechanisms whereby chronic elevations of glucose might damageβ-cells are our study will to investigate. We will explore whether that chronic oxidative stress and JNK pathway is involved in the mechanism that glucose excess can damageβ-cells and provides a target for that lessen glucose toxicity .
1. To investigate the effect of different concentration glucose on the function and apoptosis of INS-1 cells.
(1) Culturing the INS-1 cells at three glucose concentration: 5.6mmol/l, 11.2 mmol/l, 33.3 mmol/l, within 48 hours and 72 hours respectively. MTT used to measure cell viability, RT-PCT used to measure the insulin, PDX-1, IAPP gene expression of the INS-1 cells, apoptosis were examined by immuno- fluorescence and flow-cytometry analysis. After treating with IGF-1 measuring these items again.
(2) Expose INS-1 cells to elevated glucose concentrations lead to impaired cell function by time-dependent method.
We cultured the cells in 5.6mmol/l and 11.2 mmol/l glucose for 48h, the glucose dose not inhibit the cell viability and induce apoptosis.
There were remarkably increasing of the apoptise when INS-1 cells expose to 33.3mmol/l glucose, with a 2.49-fold increase to cells in the basal 5.6mmol/l glucose.In 11.2G a nd 33.3G group caused a 11.2% and 42.4% decrease of the insulin gene expression (P <0.001),also reduced the PDX-1 gene expression by 50% and 63%(p<0.001)After IGF-1 plus, insulin and PDX-1 mRNA level are increased, wherase the effctor were lessen with the elevated glucose.
2. Reactive oxygen species (ROS) were measured by enzyme linked immunosorbent assay.NAC added can improve the cells function in high glucose with decrease the ROS in the cells.
(1).The ROS production were increased with the elevated glucose concentration, longer the cells exposed to high concentration glucose, more the ROS production were. NAC decreased the ROS in any concentration of glucose.
(2).NAC treatment remarkably improve the function of INS-1 cells exposed to high glucose. NAC treatment led to cell viability increased and apoptosis cell decreased to 13% in 33.3G group. The mRNA level of insulin and PDX-1 were also increased after the INS-1 cell treated with NAC for 48h and 72h,for insulin were 41% and 77% increased(P<0.01) respectively,and for PDX-1 were 56% and 113%(P<0.01)increased respectively in 33.3G group.NAC treatment led to insulin and PDX-1 gene expression restoration nearly to the base level.
3. Western-blot methods to test the serine270 phosphorylation of IRS and phosphorylation of JNK inβcells, and investigate the mechanisms of glucose toxitity.
(1)SP600125 improves INS-1 cells function by inhibiting the JNK pathway. After SP600125 treatment caused a 45% decreased of the apoptosis cells in 33.3G group (P<0.01), and improveing the cytoactive. The mRNA level of insulin and PDX-1 were partly restored by inhibit the JNK signal pathway.
(2)High glucose lead to the the serine 270 phosphorylation of IRS correlates with JNK phosphorylation in INS-1 cells. Using Western-blot analysis, the levels of serine 270 phosphorylation of IRS were 1.17 fold increased in 33.3G JNK compares to 11.2G group(P<0.01). SP600125 treatment completely blocked the JNK phosphorylation, but partly blocked serine 270 phosphorylation of IRS.
Conclusion Chronic high glucose toxicity impair the INS-1 function and induce the cells developed apoptosis might be related to elevated glucose concentrations increase levels of reactive oxygen species in INS-1 cells. The antioxidant agent NAC protect INS-1 cells from glucose toxicity with the effect to improve the oxidative stress response in INS-1 cells.JNK pathway contribute to the glucose toxicity by inhibiting the IRS signal througe phosphorylate Ser270 of IRS in INS-1 cells.
引文
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