ClC-2氯离子通道在RGC-5细胞凋亡中的作用研究
摘要
视网膜神经节细胞(retinal ganglion cells, RGCs)的凋亡是视神经损伤、青光眼、缺血性视神经病变等眼科疾病的重要病理特征之一，也是导致视野缺损的主要原因。RGC-5细胞系是目前作为视神经保护体外实验模型的一个重要细胞系。谷氨酸是视网膜的主要兴奋性递质，正常情况下不引起毒性。但在眼压升高、视神经供血不足等导致视网膜缺血缺氧时，谷氨酸会大量释放，对视网膜神经节细胞产生毒性作用。谷氨酸的过度表达是导致RGCs凋亡的重要原因。因此，利用谷氨酸诱导的RGC-5凋亡可以作为研究视网膜神经节细胞凋亡及视神经保护的模型。
氯离子是生物体内含量最丰富的阴离子，通过跨膜转运和离子通道参与机体多种生物功能。电压门控性氯离子通道(voltage-gated chloride channnel, ClC)在哺乳动物细胞中广泛表达，ClC-2氯离子通道作为此家族中的一个亚型，是目前研究较为广泛和明确的一种氯离子通道类型，与细胞增殖、凋亡及细胞周期等多种生理功能的调节有关。关于电压门控性氯通道参与细胞凋亡过程己得到广泛证实。线粒体凋亡通路是细胞凋亡的主要途径之一。眼部组织多种细胞的凋亡都是通过线粒体凋亡通路完成，并在多种眼科疾病中发挥作用。Bcl-2基因家族对细胞凋亡的激活和调控起着关键作用，是RGCs主要的内源性凋亡通路。
鉴于此，实验以谷氨酸诱导RGC-5细胞凋亡作为研究对象，应用cDNA转染和RNAi基因沉默方法分别改变细胞内ClC-2的表达，观察细胞凋亡、细胞周期变化情况及Bcl-2及Bax蛋白表达、caspase-3、caspase-9酶活性变化，以探讨ClC-2及Bcl-2/Bax调控的线粒体凋亡通路在此过程中的作用。
实验中首先应用RT-PCR的方法证实了RGC-5细胞中存在ClC-2mRNA的表达；然后应用细胞免疫荧光染色的方法证实了ClC-2蛋白在RGC-5细胞中存在表达，并定位于细胞浆，为下一步实验提供了基础和依据。
文献报道当谷氨酸刺激浓度为lmM时，并作用于RGC-5细胞24小时的凋亡率大约为20%，是较适宜的研究浓度。因此我们将传代后的细胞贴壁生长24小时后，加入含有lmM谷氨酸的无血清DMEM培养液培养24小时，从而得到RGC-5细胞凋亡的模型。
进一步实验以谷氨酸诱导的RGC-5细胞凋亡为研究对象，应用ClC-2cDNA技术成功转染细胞，使细胞内ClC-2的mRNA及蛋白质表达均明显升高。应用MTT法、流式细胞仪检测细胞的凋亡及周期变化情况。MTT法结果显示细胞的存活率明显上升，流式细胞仪检测结果表明凋亡率下降，并且细胞周期G1期的细胞比例减少，进入S期细胞增多。以上结果提示ClC-2的过表达对谷氨酸诱导的RGC-5细胞凋亡具有保护作用。
随后实验应用RNAi技术转染谷氨酸诱导的RGC-5细胞，RT-PCR及Westernblot结果证实ClC-2的mRNA及蛋白质表达均被明显抑制，应用MTT法、流式细胞仪检测细胞的凋亡及周期变化情况。MTT法结果显示细胞的存活率明显下降，流式细胞仪检测结果表明凋亡率增加，并且细胞周期G1期的细胞比例明显增多，进入S期细胞显著减少。结果证实了抑制ClC-2的表达可以促进细胞的凋亡。以上两部分实验从正反两方面提示ClC-2氯离子通道对谷氨酸诱导的RGC-5细胞凋亡具有保护作用。
为了进一步探讨ClC-2氯离子通道如何抑制谷氨酸诱导的RGC-5细胞凋亡作用，我们进行了分子机制的研究。分别采用cDNA转染技术增加RGC-5细胞内ClC-2的表达及RNAi技术抑制RGC-5细胞内ClC-2的表达，观察Bcl-2、Bax蛋白及caspase-3、caspase-9酶活性在各组细胞中的变化。发现与谷氨酸诱导组相比，谷氨酸诱导+ClC-2cDNA转染组Bax蛋白表达、caspase-3、caspase-9酶活性均显著下降，而Bcl-2蛋白表达显著升高；相反，与谷氨酸诱导组相比，谷氨酸诱导+ClC-2RNAi组，Bax蛋白表达、caspase-3、caspase-9酶活性均显著增高，Bcl-2蛋白表达显著降低；以上实验结果说明了ClC-2氯离子通道的抗凋亡作用是通过内源性线粒体凋亡通路进行，并通过上调Bcl-2蛋白表达及下调Bax蛋白来调控细胞凋亡。
本研究探讨了在谷氨酸诱导的RGC-5细胞凋亡过程中，ClC-2氯离子通道及线粒体凋亡通路的作用，发现ClC-2氯离子通道对谷氨酸诱导的RGC-5细胞凋亡具有保护作用，而Bcl-2/Bax调控的线粒体凋亡通路可能参与此过程。我们的实验结果提示ClC-2氯离子通道及Bcl-2/Bax调控的线粒体凋亡通路可能成为视神经保护的一个新靶点，为进一步研究视神经保护提供了理论基础和实验依据。
Retinal ganglion cells (RGCs) apoptosis is an important pathological feature ofglaucoma and other eye diseases. The RGC-5cell line is currently used as an invitromodel of glaucoma and optic nerve protection. Glutamate normally functions as themajor excitatory amino acid neurotransmitter in the retina, but at high concentrationsit becomes neurotoxic after the intraocular pressure increased, over-expression ofglutamate will play a large role in RGCs apoptosis. Therefore, a glutamate-inducedRGC-5apoptosis model can be used to investigate RGC apoptosis and opticneuroprotection.
Chloride ion is the most abundant negion, participating in a variety of biologicalfunctions through transmembrane transport and ion channels. Chloride channels (ClC)have been shown extensively distributing in mammals organs, tissues and cells. Itplays an important role in many physiological and pathological functions, such asapoptosis, cell proliferation and cell cycle. Voltage-gated chloride channels involvedin the apoptosis process has been widely confirmed. Mitochondrial apoptosis pathwayis one of the main way of apoptosis, which have been shown extensively distributingin eye and play a role in many ophthalmology disease. Bcl-2gene family plays a keyrole in activation on cell apoptosis and regulation, which is the main endogenouspathway of apoptosis of RGCs.
Reverse transcription-polymerase chain reaction (RT-PCR) results revealed ClC-2mRNA expressed in RGC-5cells. Cell immunofluorescence suggested that ClC-2protein expressions in RGC-5cells was localized in the cytoplasm.
The apoptosis rate of20%is suitable for research at a concentration of1mmol/Lglutamate. The RGC-5cells were allowed to grow for24hours, followed by culturewith serum-free DMEM supplemented with1mmol/L glutamate for24hours. Thepresent experiment analyzed glutamate-induced RGC-5cell apoptosis, showing thatClC-2mRNA and protein expressions significantly increased with ClC-2cDNAtransfection. MTT、flow cytometry cell cycle and FITC/PI analysis detected these viability and apoptosis. After the ClC-2cDNA transfection, MTT assay resultsdemonstrated significantly increased survival rate, flow cytometry and apoptosis ratewas significantly decreased, the cell proportion in cell cycle in G1phase decreased, Sphase increased, which suggests that ClC-2overexpression exhibited a protectiveeffect on apoptosis.
ClC-2mRNA and protein expressions were inhibited by RNAi technology.MTT、flow cytometry cell cycle and FITC/PI analysis detected cell viability andapoptosis. After the ClC-2expressions were inhibited, MTT assay resultsdemonstrated significantly decreased survival rate, flow cytometry revealed theapoptosis rate was significantly increased, the cell proportion in cell cycle in G1phaseincreased, S phase decreased, which suggests that the inhibition of ClC-2maypromote the apoptosis of glutamate-induced RGC-5cell.
In order to further explore how ClC-2chloride channels inhibits glutamate-induced apoptosis in RGC-5cells, we conduct study on molecular mechanism.Weused cDNA transfection to increase and RNAi technology to decrease the intracellularexpression of ClC-2in RGC-5cells, then to observe the Bcl-2, Bax protein andenzyme activities of Caspase-3/9. Compared with the glutamate-induced group, theBax protein and Caspase-3/9enzyme activities significantly decreased in the ClC-2cDNA transfection+glutamate-induced group, the Bcl-2protein significantlyincreased. In contrast, compared with the glutamate-induced group, Bax protein andCaspase-3/9enzyme activities significantly increased in the ClC-2RNAi transfection+glutamate-induced group, the Bcl-2protein significantly decreased. Our findingssuggest that ClC-2chloride channels play a protective role in glutamate-induced apoptosis viamitochondria-dependent pathways involving Bcl-2, Bax, and caspases-3and-9.
In summary, we found that ClC-2has protective effects on glutamate-induced apoptosis ofRGC-5cells by influencing the mitochondrial signaling pathway, involving Bcl-2, Bax, andcaspases-3and-9. Our results suggest that increasing the function of ClC-2channels may result inan improvement of cell survival and a reduction of cell apoptosis. Thus, the neuroprotectiveeffects of ClC-2channels may lead to a novel approach for the treatment of retinopathies, such asglaucoma.
氯离子是生物体内含量最丰富的阴离子，通过跨膜转运和离子通道参与机体多种生物功能。电压门控性氯离子通道(voltage-gated chloride channnel, ClC)在哺乳动物细胞中广泛表达，ClC-2氯离子通道作为此家族中的一个亚型，是目前研究较为广泛和明确的一种氯离子通道类型，与细胞增殖、凋亡及细胞周期等多种生理功能的调节有关。关于电压门控性氯通道参与细胞凋亡过程己得到广泛证实。线粒体凋亡通路是细胞凋亡的主要途径之一。眼部组织多种细胞的凋亡都是通过线粒体凋亡通路完成，并在多种眼科疾病中发挥作用。Bcl-2基因家族对细胞凋亡的激活和调控起着关键作用，是RGCs主要的内源性凋亡通路。
鉴于此，实验以谷氨酸诱导RGC-5细胞凋亡作为研究对象，应用cDNA转染和RNAi基因沉默方法分别改变细胞内ClC-2的表达，观察细胞凋亡、细胞周期变化情况及Bcl-2及Bax蛋白表达、caspase-3、caspase-9酶活性变化，以探讨ClC-2及Bcl-2/Bax调控的线粒体凋亡通路在此过程中的作用。
实验中首先应用RT-PCR的方法证实了RGC-5细胞中存在ClC-2mRNA的表达；然后应用细胞免疫荧光染色的方法证实了ClC-2蛋白在RGC-5细胞中存在表达，并定位于细胞浆，为下一步实验提供了基础和依据。
文献报道当谷氨酸刺激浓度为lmM时，并作用于RGC-5细胞24小时的凋亡率大约为20%，是较适宜的研究浓度。因此我们将传代后的细胞贴壁生长24小时后，加入含有lmM谷氨酸的无血清DMEM培养液培养24小时，从而得到RGC-5细胞凋亡的模型。
进一步实验以谷氨酸诱导的RGC-5细胞凋亡为研究对象，应用ClC-2cDNA技术成功转染细胞，使细胞内ClC-2的mRNA及蛋白质表达均明显升高。应用MTT法、流式细胞仪检测细胞的凋亡及周期变化情况。MTT法结果显示细胞的存活率明显上升，流式细胞仪检测结果表明凋亡率下降，并且细胞周期G1期的细胞比例减少，进入S期细胞增多。以上结果提示ClC-2的过表达对谷氨酸诱导的RGC-5细胞凋亡具有保护作用。
随后实验应用RNAi技术转染谷氨酸诱导的RGC-5细胞，RT-PCR及Westernblot结果证实ClC-2的mRNA及蛋白质表达均被明显抑制，应用MTT法、流式细胞仪检测细胞的凋亡及周期变化情况。MTT法结果显示细胞的存活率明显下降，流式细胞仪检测结果表明凋亡率增加，并且细胞周期G1期的细胞比例明显增多，进入S期细胞显著减少。结果证实了抑制ClC-2的表达可以促进细胞的凋亡。以上两部分实验从正反两方面提示ClC-2氯离子通道对谷氨酸诱导的RGC-5细胞凋亡具有保护作用。
为了进一步探讨ClC-2氯离子通道如何抑制谷氨酸诱导的RGC-5细胞凋亡作用，我们进行了分子机制的研究。分别采用cDNA转染技术增加RGC-5细胞内ClC-2的表达及RNAi技术抑制RGC-5细胞内ClC-2的表达，观察Bcl-2、Bax蛋白及caspase-3、caspase-9酶活性在各组细胞中的变化。发现与谷氨酸诱导组相比，谷氨酸诱导+ClC-2cDNA转染组Bax蛋白表达、caspase-3、caspase-9酶活性均显著下降，而Bcl-2蛋白表达显著升高；相反，与谷氨酸诱导组相比，谷氨酸诱导+ClC-2RNAi组，Bax蛋白表达、caspase-3、caspase-9酶活性均显著增高，Bcl-2蛋白表达显著降低；以上实验结果说明了ClC-2氯离子通道的抗凋亡作用是通过内源性线粒体凋亡通路进行，并通过上调Bcl-2蛋白表达及下调Bax蛋白来调控细胞凋亡。
本研究探讨了在谷氨酸诱导的RGC-5细胞凋亡过程中，ClC-2氯离子通道及线粒体凋亡通路的作用，发现ClC-2氯离子通道对谷氨酸诱导的RGC-5细胞凋亡具有保护作用，而Bcl-2/Bax调控的线粒体凋亡通路可能参与此过程。我们的实验结果提示ClC-2氯离子通道及Bcl-2/Bax调控的线粒体凋亡通路可能成为视神经保护的一个新靶点，为进一步研究视神经保护提供了理论基础和实验依据。
Retinal ganglion cells (RGCs) apoptosis is an important pathological feature ofglaucoma and other eye diseases. The RGC-5cell line is currently used as an invitromodel of glaucoma and optic nerve protection. Glutamate normally functions as themajor excitatory amino acid neurotransmitter in the retina, but at high concentrationsit becomes neurotoxic after the intraocular pressure increased, over-expression ofglutamate will play a large role in RGCs apoptosis. Therefore, a glutamate-inducedRGC-5apoptosis model can be used to investigate RGC apoptosis and opticneuroprotection.
Chloride ion is the most abundant negion, participating in a variety of biologicalfunctions through transmembrane transport and ion channels. Chloride channels (ClC)have been shown extensively distributing in mammals organs, tissues and cells. Itplays an important role in many physiological and pathological functions, such asapoptosis, cell proliferation and cell cycle. Voltage-gated chloride channels involvedin the apoptosis process has been widely confirmed. Mitochondrial apoptosis pathwayis one of the main way of apoptosis, which have been shown extensively distributingin eye and play a role in many ophthalmology disease. Bcl-2gene family plays a keyrole in activation on cell apoptosis and regulation, which is the main endogenouspathway of apoptosis of RGCs.
Reverse transcription-polymerase chain reaction (RT-PCR) results revealed ClC-2mRNA expressed in RGC-5cells. Cell immunofluorescence suggested that ClC-2protein expressions in RGC-5cells was localized in the cytoplasm.
The apoptosis rate of20%is suitable for research at a concentration of1mmol/Lglutamate. The RGC-5cells were allowed to grow for24hours, followed by culturewith serum-free DMEM supplemented with1mmol/L glutamate for24hours. Thepresent experiment analyzed glutamate-induced RGC-5cell apoptosis, showing thatClC-2mRNA and protein expressions significantly increased with ClC-2cDNAtransfection. MTT、flow cytometry cell cycle and FITC/PI analysis detected these viability and apoptosis. After the ClC-2cDNA transfection, MTT assay resultsdemonstrated significantly increased survival rate, flow cytometry and apoptosis ratewas significantly decreased, the cell proportion in cell cycle in G1phase decreased, Sphase increased, which suggests that ClC-2overexpression exhibited a protectiveeffect on apoptosis.
ClC-2mRNA and protein expressions were inhibited by RNAi technology.MTT、flow cytometry cell cycle and FITC/PI analysis detected cell viability andapoptosis. After the ClC-2expressions were inhibited, MTT assay resultsdemonstrated significantly decreased survival rate, flow cytometry revealed theapoptosis rate was significantly increased, the cell proportion in cell cycle in G1phaseincreased, S phase decreased, which suggests that the inhibition of ClC-2maypromote the apoptosis of glutamate-induced RGC-5cell.
In order to further explore how ClC-2chloride channels inhibits glutamate-induced apoptosis in RGC-5cells, we conduct study on molecular mechanism.Weused cDNA transfection to increase and RNAi technology to decrease the intracellularexpression of ClC-2in RGC-5cells, then to observe the Bcl-2, Bax protein andenzyme activities of Caspase-3/9. Compared with the glutamate-induced group, theBax protein and Caspase-3/9enzyme activities significantly decreased in the ClC-2cDNA transfection+glutamate-induced group, the Bcl-2protein significantlyincreased. In contrast, compared with the glutamate-induced group, Bax protein andCaspase-3/9enzyme activities significantly increased in the ClC-2RNAi transfection+glutamate-induced group, the Bcl-2protein significantly decreased. Our findingssuggest that ClC-2chloride channels play a protective role in glutamate-induced apoptosis viamitochondria-dependent pathways involving Bcl-2, Bax, and caspases-3and-9.
In summary, we found that ClC-2has protective effects on glutamate-induced apoptosis ofRGC-5cells by influencing the mitochondrial signaling pathway, involving Bcl-2, Bax, andcaspases-3and-9. Our results suggest that increasing the function of ClC-2channels may result inan improvement of cell survival and a reduction of cell apoptosis. Thus, the neuroprotectiveeffects of ClC-2channels may lead to a novel approach for the treatment of retinopathies, such asglaucoma.
引文
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