BDNF对高糖状态下视网膜神经元保护作用的实验研究
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摘要
目的：建立高糖状态下视网膜神经元细胞模型,探讨外源性脑源性神经营养因子(BDNF)对高糖状态下视网膜神经元凋亡的保护效应,及可能的细胞内信号传递机制。同时建立糖尿病大鼠动物模型,探讨其视网膜组织病理学变化,以及与视网膜BDNF、酪氨酸激酶受体B (TrkB)、细胞外信号调节蛋白激酶(ERK)、胶质原纤维酸性蛋白(GFAP)表达变化的关系,为BDNF潜在的临床应用价值提供理论依据。
方法：本研究分两大部分进行。第一部分：1、以0、5.5、15、25、35mmol/L不同浓度葡萄糖分别作用于原代培养的Wistar大鼠视网膜神经元24、48、72h,采用四甲基偶氮唑蓝(MTT)法及流式细胞仪分析检测神经元的存活率、凋亡率,确定葡萄糖最适干预浓度及时间,建立原代培养的大鼠视网膜神经元的高糖模型。2、予以75、100、125ng/mL不同浓度BDNF干预高糖状态下视网膜神经元96h后,采用MTT法及流式细胞仪分析检测神经元的存活率、凋亡率的变化,采用免疫细胞化学染色法观察BDNF受体TrkB的蛋白表达变化,确定BDNF最适干预浓度及时间。3、采用Western Blot法及逆转录-聚合酶链反应(RT-PCR)法检测4个不同组(正常对照组,正常对照+BDNF组,高糖模型组,高糖+BDNF组)的TrkB、ERK的蛋白及mRNA, PTrkB、PERK蛋白的表达水平,分析BDNF对高糖状态下视网膜神经元中TrkB、ERK磷酸化的影响。第二部分：1、建立糖尿病大鼠动物模型,以正常大鼠为对照,分别于糖尿病成模后4、12、24W,采用苏木素/伊红(HE)染色观察大鼠后极部视网膜总厚度、视网膜神经节细胞(RGCs)计数以及视网膜组织形态学变化,透射电镜观察糖尿病24W大鼠视网膜各层组织细胞的超微结构变化。2、于糖尿病4、12、24W,采用免疫组织荧光化学法、免疫组织化学法、Western blot方法分别检测糖尿病组与正常对照组大鼠视网膜GFAP、TrkB及ERK、BDNF蛋白的表达,采用RT-PCR法检测两组大鼠视网膜TrkB、ERK、BDNFmRNA的表达。
结果：第一部分：1、随葡萄糖浓度的增加及时间的延长,视网膜神经元的存活率下降、凋亡率增多,以35mmol/L葡萄糖干预72h的神经元存活率(OD值：0.0268±0.0116)下降、凋亡率(40.123±7.576%)增加最为显著(p<0.01)。2、随着BDNF浓度的增加,高糖状态下视网膜神经元存活率增加、凋亡率下降,伴随着BDNF受体TrkB蛋白表达增高,以100ng/mlBDNF干预96h组凋亡率(3.458±1.531%)下降及TrkB蛋白表达增高最为显著(p<0.05)。3、TrkB蛋白及mRNA在其它各组的表达均较正常对照组增加(p<0.05),高糖+BDNF组比较高糖组TrkB表达亦增加(p<0.05)；ERK蛋白及mRNA表达水平在各组之间无差异(p>0.05); PERK, PTrkB蛋白在高糖组的表达与正常对照组比较无差异(p>0.05),正常对照+BDNF组与高糖+BDNF组比较其它2组PERK、PTrkB表达显著增加(p<0.05),高糖+BDNF组比较其它各组PERK、PTrkB表达显著增加(p<0.05)。第二部分：1、糖尿病组在12、24W两个时间点与正常组相比较,后极部视网膜总厚度明显变薄(60.26±4.33.52.11±5.23μm), RGCs细胞数减少(67.57±2.59、54.93±2.02个),差异有统计学意义(p<0.05)。糖尿病24W透射电镜观察显示：视网膜RGCs及神经胶质细胞有凋亡征象。2、免疫组织荧光化学法检测显示：随病程增加,GFAP蛋白在糖尿病大鼠视网膜的表达依次增强。免疫组织化学法及RT-PCR法检测显示：在病程4W时糖尿病大鼠视网膜的TrkB蛋白及mRNA表达比较正常组明显增加(p<0.05),12W时表达比较正常组明显下降,24W时下降更明显(p<0.01)；病程4、12、24W时糖尿病大鼠视网膜的ERK蛋白及1mRNA的表达均较正常组增加,差异有统计学意义(p<0.05),但糖尿病各组之间比较无差异(p>0.05)。Western blot法及RT-PCR法检测显示：随病程增加,糖尿病大鼠视网膜BDNF蛋白及mRNA表达依次下降,比较正常组差异有统计学意义(p<0.05),且糖尿病各组之间也有统计学差异(p<0.05)。
结论：1、体外高糖水平可诱导视网膜神经元的凋亡。2、外源性BDNF对高糖诱导的视网膜神经元的凋亡具有保护作用,并能有效上调神经元细胞内TrkB蛋白及mRNA、PERK蛋白、PTrkB蛋白的表达,从而可能通过细胞外信号调节激酶/丝裂原活化蛋白激酶(ERK/MAPK)信号转导途径调控视网膜神经元的凋亡。3、早期糖尿病大鼠动物模型存在神经视网膜的改变(RGCs及神经胶质细胞的凋亡),可能是研究早期糖尿病神经元病变有价值的模型。4、早期糖尿病大鼠神经视网膜病变可能与BDNF、TrkB蛋白及mRNA水平降低,GFAP蛋白、ERK蛋白及mRNA水平增高有关。
Objective:The study takes hyperglycemia retinal neurons models as subjects to explore the protective effects of exogenous brain derived neurotrophic factor (BDNF) on the apoptosis process of hyperglycemia retinal neurons and the possible intracellular signal transmission mechanism of protective function of hyperglycemia retinal neurons. Meanwhile, the study will set up the hyperglycemia rat models and deal with investigating pathological changes of retinal tissue of these rat and the allaxis rule of BDNF, Tyrosine kinase B(TrkB), extracellular signal-regulated kinase(ERK) and glial fibrillary acidic protein(GFAP),and the relationship between them which will provide evidence for potential clinical values of BDNF.
Methods:This study consists of two parts. Section One:1. Put glucose with different concentrations (0、5.5、15、25、35mmol/L)on primary culture retinal neurons of wistar rat for different time(24、48、72h), and detect the surviaval rate and cellular apoptosis rate of neurons by MTT and FCM respectively to identify the most suitable glucose concentration and time,Building hyperglycemia model of primary culture retinal neurons of wistar rat; 2. Put BDNF with different concentrations (75、100、125ng/mL) on hyperglycemia retina neurons for 96 hours, after that, the survival rate and cellular apoptosis of neurons are tested by MTT and FCM respectively, in addition, the immunocytochemistry chromosome method will be employed to oberserve the changes of TrkB protein of BDNF receptor to identify the most suitable concentration and time; 3. Western Blot and reverse transcriptase-polymerase chain reaction(RT-PCR) will be used to detect the protein expression levels of ERK, mRNA protein, PERK and PTrkB of four different groups(control group, hyperglycemia model group, hyperglycemia+ BDNF group and control+BDNFgroup) to analyze the effects of BDNF on phosphorylation of ERK and TrkB in hyperglycemia retinal neurons.
Section two:1. Build diabetes rat models and take the normal rat as the control group. HE dying method will be utilized to observe the thickness of retina, celluar numbers of retinal ganglion cells(RGCs) and histomorphological changes of rat's retina at the time of 4、12、24 weeks respectively after models building. Use the transmission electron microscope to observe ultramicro structural changes of bistiocytes of rat's retina at the time of 24 weeks; 2. Utilize immunity fluorescence histochemical method to detect expression of GFAP protein in diabetes group and control group. Immune histochemical method will be employed to detect expression of TrkB and ERK protein. Adopt western blot method to test expression of BDNF protein. Employ RT-PCR to detect expression of BDNF, TrkB and ERK mRNA in retinal tissue of rat in two groups at the time of 4、12、24 weeks.
Results:Section One:1、The survival rate of retinal neuron decreases with augmentation of glucose concentration and time while the apoptosis rate of retinal neutron increases. The survival rate of retinal neuron decreases(OD value:0.0268±0.0116) and the apoptosis of neutron increases (40.123±7.576%) most remarkbly with 35 mmol/L glucose concentration for 96 hours(p<0.01).2、The survival rate of retinal neuron increases and the apoptosis of neutron decreases with the increase of BDNF concentration. The apoptosis of neutron decreases (3.458±1.531%) and the expression of TrkB protein increases with the increase of BDNF receptor TrkB protein most markedly after putting 100ng/ml BDNF on retina neurons for 96 hours (p<0.01).3、Expression of TrkB protein and mRNA in other groups increases compared with control group (p<0.05), and compared with hyperglycemia group, hyperglycemia +BDNF group has increase of TrkB expression(p<0.05); There were no differences among four groups in terms of ERK protein and mRNA expression level; There is no difference between hyperglycemia group and control group in terms of PERK and PTrkB protein expression level, comparing other two groups,control+BDNF group and hyperglycemia +BDNF group have remarkable increase of PERK and PTrkB protein (p<0.05), Compared with other groups, hyperglycemia+ BDNF group have remarkable increase of PERK and PTrkB protein (p<0.05). Section two:1、Compared with control group, thickness of retina (60.26±4.33、52.11±5.23μm) in diabetes group becomes thin in evidence (p<0.05), numbers of RGC cells (67.57±2.59、54.93±2.02) decreases with statistical significance (p<0.05) at the time of 12 weeks and 24 weeks. It shows that there are apoptosis signs of neuroganglion cells and neuroglia cells in diabetes group for 24 weeks via transmission electron microscope.2、Immunohistochemical fluorescent method indicates the expression of GFAP protein in retinal tissue increases with augmentation of course of disease. Immunohisto-chemical method and RT-PCR demonstrate that the expression level of TrkB protein and mRNA in retinal tissue of diabetes rat increases remarkably compared with control group (p<0.05) in 4-week course of disease. In 12-week course of disease, the expression level of TrkB protein and mRNA decreases. In 24-week course of disease, it decreases obviously. The expression of ERK protein and mRNA increases differently (p<0.05) compared with control group while there is no difference (p>0.05) among the diabetes group. The results detected by Western Blot and RT-PCR show that expression of BDNF protein and mRNA decreases in turn and that statistical significance exists compared with control group and there are differences among the diabetes group (p<0.05).
Conclusions:
1、Hyperglycemia can induce apoptosis of retinal neurons.
2、Exogenous BDNF can conserve the apoptosis of hyperglycemia retina neurons and increase expression of mRNA and protein in TrkB, PERK protein and PTrkB protein, thus controling apoptosis of retinal neurons by ERK/mitogen activated protein kinase (MAPK) signals pathway.
3、The early diabetes rat models set up in the study have neuron retina changes (apoptosis of RGCs and neuroglia cells). Therefore these models are valuable for studying pathological changes of diabetes neurons.
4、The pathological changes of amphiblestrodes of the early diabetes rat are related to the decreasing level of mRNA and protein in BDNF and TrkB, and increasing level of protein in GFAP and mRNA and protein in ERK.
方法：本研究分两大部分进行。第一部分：1、以0、5.5、15、25、35mmol/L不同浓度葡萄糖分别作用于原代培养的Wistar大鼠视网膜神经元24、48、72h,采用四甲基偶氮唑蓝(MTT)法及流式细胞仪分析检测神经元的存活率、凋亡率,确定葡萄糖最适干预浓度及时间,建立原代培养的大鼠视网膜神经元的高糖模型。2、予以75、100、125ng/mL不同浓度BDNF干预高糖状态下视网膜神经元96h后,采用MTT法及流式细胞仪分析检测神经元的存活率、凋亡率的变化,采用免疫细胞化学染色法观察BDNF受体TrkB的蛋白表达变化,确定BDNF最适干预浓度及时间。3、采用Western Blot法及逆转录-聚合酶链反应(RT-PCR)法检测4个不同组(正常对照组,正常对照+BDNF组,高糖模型组,高糖+BDNF组)的TrkB、ERK的蛋白及mRNA, PTrkB、PERK蛋白的表达水平,分析BDNF对高糖状态下视网膜神经元中TrkB、ERK磷酸化的影响。第二部分：1、建立糖尿病大鼠动物模型,以正常大鼠为对照,分别于糖尿病成模后4、12、24W,采用苏木素/伊红(HE)染色观察大鼠后极部视网膜总厚度、视网膜神经节细胞(RGCs)计数以及视网膜组织形态学变化,透射电镜观察糖尿病24W大鼠视网膜各层组织细胞的超微结构变化。2、于糖尿病4、12、24W,采用免疫组织荧光化学法、免疫组织化学法、Western blot方法分别检测糖尿病组与正常对照组大鼠视网膜GFAP、TrkB及ERK、BDNF蛋白的表达,采用RT-PCR法检测两组大鼠视网膜TrkB、ERK、BDNFmRNA的表达。
结果：第一部分：1、随葡萄糖浓度的增加及时间的延长,视网膜神经元的存活率下降、凋亡率增多,以35mmol/L葡萄糖干预72h的神经元存活率(OD值：0.0268±0.0116)下降、凋亡率(40.123±7.576%)增加最为显著(p<0.01)。2、随着BDNF浓度的增加,高糖状态下视网膜神经元存活率增加、凋亡率下降,伴随着BDNF受体TrkB蛋白表达增高,以100ng/mlBDNF干预96h组凋亡率(3.458±1.531%)下降及TrkB蛋白表达增高最为显著(p<0.05)。3、TrkB蛋白及mRNA在其它各组的表达均较正常对照组增加(p<0.05),高糖+BDNF组比较高糖组TrkB表达亦增加(p<0.05)；ERK蛋白及mRNA表达水平在各组之间无差异(p>0.05); PERK, PTrkB蛋白在高糖组的表达与正常对照组比较无差异(p>0.05),正常对照+BDNF组与高糖+BDNF组比较其它2组PERK、PTrkB表达显著增加(p<0.05),高糖+BDNF组比较其它各组PERK、PTrkB表达显著增加(p<0.05)。第二部分：1、糖尿病组在12、24W两个时间点与正常组相比较,后极部视网膜总厚度明显变薄(60.26±4.33.52.11±5.23μm), RGCs细胞数减少(67.57±2.59、54.93±2.02个),差异有统计学意义(p<0.05)。糖尿病24W透射电镜观察显示：视网膜RGCs及神经胶质细胞有凋亡征象。2、免疫组织荧光化学法检测显示：随病程增加,GFAP蛋白在糖尿病大鼠视网膜的表达依次增强。免疫组织化学法及RT-PCR法检测显示：在病程4W时糖尿病大鼠视网膜的TrkB蛋白及mRNA表达比较正常组明显增加(p<0.05),12W时表达比较正常组明显下降,24W时下降更明显(p<0.01)；病程4、12、24W时糖尿病大鼠视网膜的ERK蛋白及1mRNA的表达均较正常组增加,差异有统计学意义(p<0.05),但糖尿病各组之间比较无差异(p>0.05)。Western blot法及RT-PCR法检测显示：随病程增加,糖尿病大鼠视网膜BDNF蛋白及mRNA表达依次下降,比较正常组差异有统计学意义(p<0.05),且糖尿病各组之间也有统计学差异(p<0.05)。
结论：1、体外高糖水平可诱导视网膜神经元的凋亡。2、外源性BDNF对高糖诱导的视网膜神经元的凋亡具有保护作用,并能有效上调神经元细胞内TrkB蛋白及mRNA、PERK蛋白、PTrkB蛋白的表达,从而可能通过细胞外信号调节激酶/丝裂原活化蛋白激酶(ERK/MAPK)信号转导途径调控视网膜神经元的凋亡。3、早期糖尿病大鼠动物模型存在神经视网膜的改变(RGCs及神经胶质细胞的凋亡),可能是研究早期糖尿病神经元病变有价值的模型。4、早期糖尿病大鼠神经视网膜病变可能与BDNF、TrkB蛋白及mRNA水平降低,GFAP蛋白、ERK蛋白及mRNA水平增高有关。
Objective:The study takes hyperglycemia retinal neurons models as subjects to explore the protective effects of exogenous brain derived neurotrophic factor (BDNF) on the apoptosis process of hyperglycemia retinal neurons and the possible intracellular signal transmission mechanism of protective function of hyperglycemia retinal neurons. Meanwhile, the study will set up the hyperglycemia rat models and deal with investigating pathological changes of retinal tissue of these rat and the allaxis rule of BDNF, Tyrosine kinase B(TrkB), extracellular signal-regulated kinase(ERK) and glial fibrillary acidic protein(GFAP),and the relationship between them which will provide evidence for potential clinical values of BDNF.
Methods:This study consists of two parts. Section One:1. Put glucose with different concentrations (0、5.5、15、25、35mmol/L)on primary culture retinal neurons of wistar rat for different time(24、48、72h), and detect the surviaval rate and cellular apoptosis rate of neurons by MTT and FCM respectively to identify the most suitable glucose concentration and time,Building hyperglycemia model of primary culture retinal neurons of wistar rat; 2. Put BDNF with different concentrations (75、100、125ng/mL) on hyperglycemia retina neurons for 96 hours, after that, the survival rate and cellular apoptosis of neurons are tested by MTT and FCM respectively, in addition, the immunocytochemistry chromosome method will be employed to oberserve the changes of TrkB protein of BDNF receptor to identify the most suitable concentration and time; 3. Western Blot and reverse transcriptase-polymerase chain reaction(RT-PCR) will be used to detect the protein expression levels of ERK, mRNA protein, PERK and PTrkB of four different groups(control group, hyperglycemia model group, hyperglycemia+ BDNF group and control+BDNFgroup) to analyze the effects of BDNF on phosphorylation of ERK and TrkB in hyperglycemia retinal neurons.
Section two:1. Build diabetes rat models and take the normal rat as the control group. HE dying method will be utilized to observe the thickness of retina, celluar numbers of retinal ganglion cells(RGCs) and histomorphological changes of rat's retina at the time of 4、12、24 weeks respectively after models building. Use the transmission electron microscope to observe ultramicro structural changes of bistiocytes of rat's retina at the time of 24 weeks; 2. Utilize immunity fluorescence histochemical method to detect expression of GFAP protein in diabetes group and control group. Immune histochemical method will be employed to detect expression of TrkB and ERK protein. Adopt western blot method to test expression of BDNF protein. Employ RT-PCR to detect expression of BDNF, TrkB and ERK mRNA in retinal tissue of rat in two groups at the time of 4、12、24 weeks.
Results:Section One:1、The survival rate of retinal neuron decreases with augmentation of glucose concentration and time while the apoptosis rate of retinal neutron increases. The survival rate of retinal neuron decreases(OD value:0.0268±0.0116) and the apoptosis of neutron increases (40.123±7.576%) most remarkbly with 35 mmol/L glucose concentration for 96 hours(p<0.01).2、The survival rate of retinal neuron increases and the apoptosis of neutron decreases with the increase of BDNF concentration. The apoptosis of neutron decreases (3.458±1.531%) and the expression of TrkB protein increases with the increase of BDNF receptor TrkB protein most markedly after putting 100ng/ml BDNF on retina neurons for 96 hours (p<0.01).3、Expression of TrkB protein and mRNA in other groups increases compared with control group (p<0.05), and compared with hyperglycemia group, hyperglycemia +BDNF group has increase of TrkB expression(p<0.05); There were no differences among four groups in terms of ERK protein and mRNA expression level; There is no difference between hyperglycemia group and control group in terms of PERK and PTrkB protein expression level, comparing other two groups,control+BDNF group and hyperglycemia +BDNF group have remarkable increase of PERK and PTrkB protein (p<0.05), Compared with other groups, hyperglycemia+ BDNF group have remarkable increase of PERK and PTrkB protein (p<0.05). Section two:1、Compared with control group, thickness of retina (60.26±4.33、52.11±5.23μm) in diabetes group becomes thin in evidence (p<0.05), numbers of RGC cells (67.57±2.59、54.93±2.02) decreases with statistical significance (p<0.05) at the time of 12 weeks and 24 weeks. It shows that there are apoptosis signs of neuroganglion cells and neuroglia cells in diabetes group for 24 weeks via transmission electron microscope.2、Immunohistochemical fluorescent method indicates the expression of GFAP protein in retinal tissue increases with augmentation of course of disease. Immunohisto-chemical method and RT-PCR demonstrate that the expression level of TrkB protein and mRNA in retinal tissue of diabetes rat increases remarkably compared with control group (p<0.05) in 4-week course of disease. In 12-week course of disease, the expression level of TrkB protein and mRNA decreases. In 24-week course of disease, it decreases obviously. The expression of ERK protein and mRNA increases differently (p<0.05) compared with control group while there is no difference (p>0.05) among the diabetes group. The results detected by Western Blot and RT-PCR show that expression of BDNF protein and mRNA decreases in turn and that statistical significance exists compared with control group and there are differences among the diabetes group (p<0.05).
Conclusions:
1、Hyperglycemia can induce apoptosis of retinal neurons.
2、Exogenous BDNF can conserve the apoptosis of hyperglycemia retina neurons and increase expression of mRNA and protein in TrkB, PERK protein and PTrkB protein, thus controling apoptosis of retinal neurons by ERK/mitogen activated protein kinase (MAPK) signals pathway.
3、The early diabetes rat models set up in the study have neuron retina changes (apoptosis of RGCs and neuroglia cells). Therefore these models are valuable for studying pathological changes of diabetes neurons.
4、The pathological changes of amphiblestrodes of the early diabetes rat are related to the decreasing level of mRNA and protein in BDNF and TrkB, and increasing level of protein in GFAP and mRNA and protein in ERK.
引文
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