FDM豚鼠RPE-脉络膜RA信号通路的研究
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摘要
研究目的
建立早期形觉剥夺性近视(form-deprivation myopia, FDM)动物模型,检测豚鼠视网膜色素上皮-脉络膜中转化生长因子β2 (transforming growth factor-beta2, TGF-β2)及活化蛋白-1 (activator protein-1, AP-1)的水平;形觉剥夺同时分别给予AP-1的抑制剂姜黄素和视黄酸受体β(retinoic acid receptorβ, RARβ)特异性抑制剂LE540,比较不同处理对屈光状态的影响,并检测视网膜色素上皮-脉络膜中TGF-β2和AP-1的水平,探讨TGF-β2和AP-1在形觉剥夺性近视豚鼠视网膜色素上皮-脉络膜中的作用及其与视磺酸(retinoic acid, RA)信号传递过程的关系。
方法
第一部分：同批次3周龄豚鼠12只,采用戴头套法遮盖左眼,右眼为自身对照眼。饲养至21天作为形觉剥夺动物模型。观测指标：1.实验前后均测量屈光度,实验结束后摘除眼球,测量眼轴长；2.应用ELISA法检测视网膜色素上皮-脉络膜中TGF-β2含量,western blotting方法检测视网膜色素上皮-脉络膜中AP-1含量的变化。
第二部分：另选同种豚鼠40只,随机分为4组,Ⅰ组6只,为正常对照组,Ⅱ、Ⅲ、Ⅳ组各12只。Ⅱ组为实验对照组,左眼球后注射0.1%DMSO0.1ml;Ⅲ组左眼球后注射0.1m(1.5g/L)姜黄素；Ⅳ组左眼球后注射0.1ml (0.1 g/L) LE540;Ⅱ、Ⅲ、Ⅳ组均隔日给药一次,共3次,并遮盖左眼至第21天。右眼为自身对照眼。观测指标同第一部分。计量资料数据以x±s表示,采用SPSS16.0统计学软件进行统计学处理,并进行正态分布及Levene方差齐性检验后行t检验和方差分析。
结果
第一部分：12只动物实验眼诱导出明显的相对近视,且与自身对照眼比较差异有统计学意义(t=-0.575,P=0.001)。实验眼眼轴均长于自身对照眼(t=-4.920,P=0.000)。实验眼视网膜色素上皮-脉络膜中TGF-β2水平较自身对照眼明显降低(t=-4.933, P=0.004), Western blotting所得c-Fos和GAPDH的灰度图显示,实验眼视网膜色素上皮-脉络膜中AP-1活性较自身对照眼减低(t=-2.832,P=0.037)。
第二部分：实验干预后Ⅱ,Ⅲ和Ⅳ组的实验眼形成相对近视,三组左右眼屈光度差异均有显著统计学意义(P<0.05)。Ⅲ组和Ⅳ组之间实验眼实验前后屈光度变化差异有统计学意义(P<0.05)。Ⅱ组、Ⅲ组和Ⅳ组干预后左右眼眼轴长度差异均有统计学意义(P<0.05)。Ⅱ组、Ⅲ组和Ⅳ组实验眼视网膜色素上皮-脉络膜中TGF-β2含量较自身对照眼明显降低(P<0.05)；Ⅰ组实验后双眼视网膜色素上皮-脉络膜中的TGF-β2含量与自身对照眼相比差异无统计学意义(P>0.05)。Ⅱ组、Ⅲ组和Ⅳ组实验后实验眼视网膜色素上皮-脉络膜中的AP-1活性表达与自身对照眼相比均明显降低(P<0.05)；Ⅰ组实验后双眼视网膜色素上皮-脉络膜中的AP-1活性表达与自身对照眼相比差异无统计学意义(P>0.05)。
结论
豚鼠形觉剥夺可导致近视发生；豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中AP-1活性和TGF-β2表达下调；AP-1抑制剂姜黄素的使用可以影响豚鼠形觉剥夺性近视的形成作用,豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中TGF-β2表达受AP-1活性的影响；RARβ抑制剂LE540的使用可以影响豚鼠早期形觉剥夺性近视的形成作用；豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中RARβ可以调控AP-1和TGF-β2的活性表达,AP-1和TGF-β2可能是调控豚鼠FDM形成的RA信号通路的重要因子,RA--RARp--AP-1--TGF-β2的视磺酸信号通路可能是调控豚鼠FDM形成的重要通路之一。
The aims of this study were detecting the transforming growth factor-beta2 (TGF-β2) and activator protein-1(AP-1) level in the retinal pigment epithelium (RPE)-choroid of early form deprivation myopia (FDM) guinea pigs. To compare refractive state among different intervention groups:FD, injection of AP-1 inhibitor curcumin and injection of RARP inhibitor LE540 conbinded with FD. To investigate TGF-β2 and AP-1 levels in the RPE-choroid of guinea pigs in those groups. And explore the role of TGF-β2 and AP-1 in RPE-Choroid of guinea pig's FD eye and retinoic acid (RA) signaling pathway.
Part one:Monocular form deprivation models were established in 12 pigmented guinea pigs of 3-week-old by covering the left eyes with facemasks for 21 days,and the fellow eyes were used as internal control. Observation index:1. Refraction was measured before and after experiment by using retinoscopy. Eyeballs were extracted immediately at the corresponding time points and ocular axial length was measured with micrometer.2. Level of TGF-β2 in RPE-Choroid was detected by enzyme-linked immunosorbent assay(ELISA),and level of AP-1 was detected by western blotting.
Part two:Other 40 guinea pigs were randomly divided into four groups:Left eyes of guinea pigs in groupⅡ(n=12)were injected postocular with 0.1ml 0.1% DMSO and occluded with facemask, as the control group.Left eyes of guinea pigs in groupⅢ(n=12) and groupⅣ(n=12)were respectively injected postocular with 0.1 ml curcumin(1.5g/L) and 0.1 ml LE540 (0.1g/L) and occluded with facemask. Other 6 guinea pigs in groupⅠwere normal group.All the right eyes were used as self-control.The experimental groups alternate day treatment three times. Observation index according to the first part. The measurement data was showed as mean±standard deviation(x±s). Assayed data with SPSS 16.0, and adopted analysis of variance ANOVA and T Test.
Results
Part one:Relative myopia was induced in experimental eyes.The diopters were significantly different between the experimental eyes and the fellow eyes(t=-0.575, P=0.001)and the axial lengths were considerably increased after experiment (t=-4.920, P=0.000). The level of TGF-β2 in the RPE-Choroid of the experimental eyes was Significantly lower than the fellow eyes (t=-4.933, P=0.004). The gray-scale maps of c-fos and GAPDH from western blotting showed the level of AP-1 in the RPE-Choroid of the experimental eyes was Significantly lower (t=-2.832, P=0.037)
Part two:Relative myopia was induced in experimental eyes of groupⅡ,ⅢandⅣ, showing statistically differences compared with the control eyes (p<0.05) Difference of axial lengths between left and right eyes in groupⅠafter the experimental intervention was not significant (P>0.05),but in groupⅡ,ⅢandⅣthe differences were significant respectively (P<0.05).The level of TGF-β2 in the RPE-Choroid of the experimental eyes in groupⅡ,ⅢandⅣwere significantly lower than the fellow eyes (P<0.05),but in groupⅠit had no statistically significant differences (P>0.05). The level of AP-1 in the RPE-Choroid of the experimental eyes in groupⅡ,ⅢandⅣwere significantly lower than the fellow eyes (P<0.05), but in groupⅠit had no statistically significant differences (P>0.05)
Conclusion
Form deprivation guinea pigs could be induced in myopia. The level of TGF-β2 and AP-1 in the RPE-Choroid of guinea pig's early FD eye were dropped. The use of curcumin could affect the power of refraction. The level of TGF-β2 was influenced by the activity of AP-1 in the RPE-Choroid of guinea pig's early FD eye. The power of refraction induced by FDM could inhibited by RARβinhibitor LE540. The expression of TGF-β2 and AP-1 might be regulated by RARβin the RPE-Choroid of guinea pig's early FD eye. TGF-β2 and AP-1 might be the important factors in RA signaling pathway that could regulate the formation of FDM guinea pigs, the RA signaling pathway might be RA-RARβ-- AP-1--TGF-β2.
建立早期形觉剥夺性近视(form-deprivation myopia, FDM)动物模型,检测豚鼠视网膜色素上皮-脉络膜中转化生长因子β2 (transforming growth factor-beta2, TGF-β2)及活化蛋白-1 (activator protein-1, AP-1)的水平;形觉剥夺同时分别给予AP-1的抑制剂姜黄素和视黄酸受体β(retinoic acid receptorβ, RARβ)特异性抑制剂LE540,比较不同处理对屈光状态的影响,并检测视网膜色素上皮-脉络膜中TGF-β2和AP-1的水平,探讨TGF-β2和AP-1在形觉剥夺性近视豚鼠视网膜色素上皮-脉络膜中的作用及其与视磺酸(retinoic acid, RA)信号传递过程的关系。
方法
第一部分：同批次3周龄豚鼠12只,采用戴头套法遮盖左眼,右眼为自身对照眼。饲养至21天作为形觉剥夺动物模型。观测指标：1.实验前后均测量屈光度,实验结束后摘除眼球,测量眼轴长；2.应用ELISA法检测视网膜色素上皮-脉络膜中TGF-β2含量,western blotting方法检测视网膜色素上皮-脉络膜中AP-1含量的变化。
第二部分：另选同种豚鼠40只,随机分为4组,Ⅰ组6只,为正常对照组,Ⅱ、Ⅲ、Ⅳ组各12只。Ⅱ组为实验对照组,左眼球后注射0.1%DMSO0.1ml;Ⅲ组左眼球后注射0.1m(1.5g/L)姜黄素；Ⅳ组左眼球后注射0.1ml (0.1 g/L) LE540;Ⅱ、Ⅲ、Ⅳ组均隔日给药一次,共3次,并遮盖左眼至第21天。右眼为自身对照眼。观测指标同第一部分。计量资料数据以x±s表示,采用SPSS16.0统计学软件进行统计学处理,并进行正态分布及Levene方差齐性检验后行t检验和方差分析。
结果
第一部分：12只动物实验眼诱导出明显的相对近视,且与自身对照眼比较差异有统计学意义(t=-0.575,P=0.001)。实验眼眼轴均长于自身对照眼(t=-4.920,P=0.000)。实验眼视网膜色素上皮-脉络膜中TGF-β2水平较自身对照眼明显降低(t=-4.933, P=0.004), Western blotting所得c-Fos和GAPDH的灰度图显示,实验眼视网膜色素上皮-脉络膜中AP-1活性较自身对照眼减低(t=-2.832,P=0.037)。
第二部分：实验干预后Ⅱ,Ⅲ和Ⅳ组的实验眼形成相对近视,三组左右眼屈光度差异均有显著统计学意义(P<0.05)。Ⅲ组和Ⅳ组之间实验眼实验前后屈光度变化差异有统计学意义(P<0.05)。Ⅱ组、Ⅲ组和Ⅳ组干预后左右眼眼轴长度差异均有统计学意义(P<0.05)。Ⅱ组、Ⅲ组和Ⅳ组实验眼视网膜色素上皮-脉络膜中TGF-β2含量较自身对照眼明显降低(P<0.05)；Ⅰ组实验后双眼视网膜色素上皮-脉络膜中的TGF-β2含量与自身对照眼相比差异无统计学意义(P>0.05)。Ⅱ组、Ⅲ组和Ⅳ组实验后实验眼视网膜色素上皮-脉络膜中的AP-1活性表达与自身对照眼相比均明显降低(P<0.05)；Ⅰ组实验后双眼视网膜色素上皮-脉络膜中的AP-1活性表达与自身对照眼相比差异无统计学意义(P>0.05)。
结论
豚鼠形觉剥夺可导致近视发生；豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中AP-1活性和TGF-β2表达下调；AP-1抑制剂姜黄素的使用可以影响豚鼠形觉剥夺性近视的形成作用,豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中TGF-β2表达受AP-1活性的影响；RARβ抑制剂LE540的使用可以影响豚鼠早期形觉剥夺性近视的形成作用；豚鼠早期形觉剥夺眼视网膜色素上皮-脉络膜中RARβ可以调控AP-1和TGF-β2的活性表达,AP-1和TGF-β2可能是调控豚鼠FDM形成的RA信号通路的重要因子,RA--RARp--AP-1--TGF-β2的视磺酸信号通路可能是调控豚鼠FDM形成的重要通路之一。
The aims of this study were detecting the transforming growth factor-beta2 (TGF-β2) and activator protein-1(AP-1) level in the retinal pigment epithelium (RPE)-choroid of early form deprivation myopia (FDM) guinea pigs. To compare refractive state among different intervention groups:FD, injection of AP-1 inhibitor curcumin and injection of RARP inhibitor LE540 conbinded with FD. To investigate TGF-β2 and AP-1 levels in the RPE-choroid of guinea pigs in those groups. And explore the role of TGF-β2 and AP-1 in RPE-Choroid of guinea pig's FD eye and retinoic acid (RA) signaling pathway.
Part one:Monocular form deprivation models were established in 12 pigmented guinea pigs of 3-week-old by covering the left eyes with facemasks for 21 days,and the fellow eyes were used as internal control. Observation index:1. Refraction was measured before and after experiment by using retinoscopy. Eyeballs were extracted immediately at the corresponding time points and ocular axial length was measured with micrometer.2. Level of TGF-β2 in RPE-Choroid was detected by enzyme-linked immunosorbent assay(ELISA),and level of AP-1 was detected by western blotting.
Part two:Other 40 guinea pigs were randomly divided into four groups:Left eyes of guinea pigs in groupⅡ(n=12)were injected postocular with 0.1ml 0.1% DMSO and occluded with facemask, as the control group.Left eyes of guinea pigs in groupⅢ(n=12) and groupⅣ(n=12)were respectively injected postocular with 0.1 ml curcumin(1.5g/L) and 0.1 ml LE540 (0.1g/L) and occluded with facemask. Other 6 guinea pigs in groupⅠwere normal group.All the right eyes were used as self-control.The experimental groups alternate day treatment three times. Observation index according to the first part. The measurement data was showed as mean±standard deviation(x±s). Assayed data with SPSS 16.0, and adopted analysis of variance ANOVA and T Test.
Results
Part one:Relative myopia was induced in experimental eyes.The diopters were significantly different between the experimental eyes and the fellow eyes(t=-0.575, P=0.001)and the axial lengths were considerably increased after experiment (t=-4.920, P=0.000). The level of TGF-β2 in the RPE-Choroid of the experimental eyes was Significantly lower than the fellow eyes (t=-4.933, P=0.004). The gray-scale maps of c-fos and GAPDH from western blotting showed the level of AP-1 in the RPE-Choroid of the experimental eyes was Significantly lower (t=-2.832, P=0.037)
Part two:Relative myopia was induced in experimental eyes of groupⅡ,ⅢandⅣ, showing statistically differences compared with the control eyes (p<0.05) Difference of axial lengths between left and right eyes in groupⅠafter the experimental intervention was not significant (P>0.05),but in groupⅡ,ⅢandⅣthe differences were significant respectively (P<0.05).The level of TGF-β2 in the RPE-Choroid of the experimental eyes in groupⅡ,ⅢandⅣwere significantly lower than the fellow eyes (P<0.05),but in groupⅠit had no statistically significant differences (P>0.05). The level of AP-1 in the RPE-Choroid of the experimental eyes in groupⅡ,ⅢandⅣwere significantly lower than the fellow eyes (P<0.05), but in groupⅠit had no statistically significant differences (P>0.05)
Conclusion
Form deprivation guinea pigs could be induced in myopia. The level of TGF-β2 and AP-1 in the RPE-Choroid of guinea pig's early FD eye were dropped. The use of curcumin could affect the power of refraction. The level of TGF-β2 was influenced by the activity of AP-1 in the RPE-Choroid of guinea pig's early FD eye. The power of refraction induced by FDM could inhibited by RARβinhibitor LE540. The expression of TGF-β2 and AP-1 might be regulated by RARβin the RPE-Choroid of guinea pig's early FD eye. TGF-β2 and AP-1 might be the important factors in RA signaling pathway that could regulate the formation of FDM guinea pigs, the RA signaling pathway might be RA-RARβ-- AP-1--TGF-β2.
引文
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