摘要
本实验成功建立了糖尿病视网膜病变的小鼠模型,应用免疫组织化学法和Western Blot方法检测糖尿病视网膜病变小鼠视网膜中Notch1、Dll4、PARP、Akt、NF-κB和caspase-3表达量的变化,同时体外培养的人视网膜血管内皮细胞HRVEC,建立高糖培养的视网膜内皮细胞模型,应用免疫印记方法检测高糖培养的视网膜血管内皮细胞由Notch1、Dll4、PARP、Akt、NF-κB和caspase-3表达量的变化,发现糖尿病小鼠模型的视网膜和高糖培养的HRVECs中的PARP和caspase-3表达量比正常对照组增高显著,并与葡萄糖浓度正相关；而Notch1、Dll4及p-Akt表达量随葡萄糖浓度的降低而显著降低,说明高糖引起的细胞凋亡与PARP增加和Notch1、p-Akt下降有关。进一步通过免疫共沉淀及激光共聚焦的方法证明了PARP和NF-κB是相互作用的蛋白质,在高糖情况下,与PARP结合的NF-κB蛋白明显增多,说明PARP通过激活NF-κB诱导细胞凋亡。另外通过Western Blot检测高糖下Notch1拮抗PARP-1和NF-κB介导的细胞凋亡,发现Notch1能够抑制高糖高糖引起的细胞凋亡。另外本实验还体外构建了siNotch1表达载体,应用免疫共沉淀及免疫印记的方法检测siNotch1对D114的抑制作用,发现siNotch1能抑制D114的抗凋亡作用,即说明Notch信号对高糖导致的细胞凋亡有保护作用。另外,利用Akt特异抑制剂wortmannin研究Akt与Notch1的关系,发现wortmannin能抑制高糖情况下Notch1对细胞的保护作用。
本实验的创新之处在于：
1、证明了Notch1、p-Akt及D114蛋白表达量在高糖培养的HRVEC中比正常HRVEC显著降低。
2、本实验发现并且证明了在高糖培养的视网膜血管内皮细胞中,Notch1/Akt信号途径能够抑制PARP-1和NF-κB介导的HRVECs凋亡
Diabetic retinopathy is one of serious microvascular complications caused by diabetes at later stage and is very common in clinic which leads to visual loss and blindness ultimately. As people's living standards and diet changes, the prevalence of diabetes increased and leads to the increase of the incidence of diabetic retinopathy significantly. Its incidence increased with age and longer duration of diabetes, the longer the duration of diabetes continued, the higher the changes in eye fundus occurs. The main symptoms of diabetic retinopathy are flash flu and vision loss and its fudus changes mainly contain capillary hemangioma, bleeding spots, hard exudates, cotton wool spots, retinal vascular disease, macular degeneration, vitreous and optic neuropathy and etc.
So far, the pathogenesis mechanism of diabetic retinopathy mainly contains oxidative stress, advanced glycosylation end products formation, polyol pathway hyperthyroidism, protein kinase C activation, the effect of vascular endothelial growth factor (VEGF), basic fibroblast growth factor(bFGF), insulin-like grow factor-1(IGF-1), tumor mecrosis factor-α(TNF-α), transforming growth factor-β(TGF-β) and platelet-derived growth factor-B (PDGF-B). Some signal transduction pathway also involved in the pathological process of diabetic retinopathy. Recent studies indicated that PARP also participated in this process. The mechanism of diabetic retinopathy is still not completely clear because it is very intrcated. Studies indicated that Notch1/Dll4 played an important role in the process of retinal vascular development. The missing of either Notch1 or Dll4 will lead to serious deficiencies in retinal blood vessels which causes vascular diseases. So we speculate that Notchl also participated in the pathological process of diabetic retinopathy. This study successfully established early mouse model of diabetic retinopathy and high glucose in vitro cell model which were used to study the relationship between Notchl and the diabetic retinopathy. This study provided a new idea and theoretical foundation for further study the mechanism, and also provides a new target for treatment of the diseases.
1. The expression of Notch1、D114、PARP、Akt、NF-κB and caspase-3 in the retina of diabetic mouse and in human retinal vascular endothelial cell exposed to high glucose.
Bcl57/6 mice were intraperitoneal injected with streptozotocin to establish mouse model of early diabetic retinopathy which was always the in vivo animal model to study the pathogenesis of diabetic. And culturing retinal vascular endothelial cells exposed to high glucose in vitro was always the in vitro model to study the pathogenesis mechanism of diabetic. We still use these two models to detect the relationship among each protein and high glucose, and the expression changes. It has been proved that PARP expressed in retinal vascular endothelial cells in STZ-induced diabetic rats indicating that PARP participated in the pathogenesis mechanism of diabetic. High glucose also can activate NF-κB which can lead to the expression of proapoptosis gene and cause cell apoptosis. It has been proved that Akt also involved in, ROS generated in high glucose can dephosphorylated Akt and inhibit the activation of Akt, leading to human umbilical vascular endothelial cells(HUVECs) apoptosis. These protein and signal pathways were all related to the pathological process of diabetic retinopathy.
Thus, we take advantage of animal and cell model and use immunohistochemical and western blot methods to detect the expression changes of Notch1, Dll4, PARP, Akt, NF-κB and caspase-3 in the retina of diabetic mouse and in human retinal vascular endothelial cell exposed to high glucose. We found that PARP and caspase-3 protein have low expression in normal mouse retina and HRVEC, and they have high expression in in the retina of diabetic mouse and in human retinal vascular endothelial cell exposed to high glucose. We also found that Notch1, p-Akt and Dll4 protein have high expression in normal mouse retina and HRVEC, and they have low expression in in the retina of diabetic mouse and in human retinal vascular endothelial cell exposed to high glucose. These results illustrated that the occurrence of diabetic retinopathy was related with the decreasing of Notch1, p-Akt and Dll4 protein and the increasing of PARP expression.
2. Notch1 signal pathway inhibits retinal vascular endothelial cells apoptosis through regulating PARP and NF-κB interaction.
Notch is an important transduction pathway highly conserved in animals which mainly effects blood vessels growth during embryonic development and regulates arteriovenous differentiation and cell proliferation and death. This signal pathway also plays an important role in the retinal vascular development. Notch signal can maintain the normal physiological environment of the retinal blood vessels. The missing of Notch can lead to retinal vascular and cell dysplasia, and retinal vascular homeostasis disorders indicating that Notch1 may involved in the pathogenesis mechanism of diabetic retinopathy. Our studies conformed that high glucose causes Notch1 decreasing also proved this view. In addition, it is also reported that high glucose can increase PARP, then PARP activate NF-κB which can then activate caspase-3 leading to cell apoptosis. Notchl may have relation with it.
Thus, we take advantage of immunoprecipitation and confocal laser scanning microscope to detect PARP and NF-κB interation under high glucose. We found that PARP and NF-κB are interacted proteins, and PARP enters into nucleus after activation to combine with NF-κB which can activate apoptosis gene to induce cell apoptosis. In addition, we use Western Blot and immunoprecipitation to detect the relationship among PARP, NF-κB and Notch1, finding that Notchl can inhibit PARP and NF-κB mediated cell apoptosis under high glucose, which indicates Notch1 can protect the retina from injury under high glucose.
3. SiNotch1 and Wortmannin, a specific inhibitor of Akt, inhibit the protective effect of Notch1 on retina
RNA interference is a defense mechanism that is highly conserved in evolution which is used to against the foreign gene or foreign virus. RNAi technology was intend to synthesize siRNA in vitro using Chemical and enzymatic methods through RNAi theory or construct plasmid and viral vector carrying siRNA, which then transfected into the cells to make the target gene silence. It was a common method that used in studying signal transduction. We also take advantage of this method to investigate the protective effect of Notchl on retina. Simultaneously, it is proved that ROS can dephosphorylate Akt under high glucose to inhibit activation of Akt, which can induce HUVECs apoptosis, the whole effect can be inhibited by wortmannin.
siNotch1 expression vector was constructed in vitro and was transfected into each group to detect PARP and NF-κB express changes, finding that siNotchl can inhibit the effect of Notchl against PARP and NF-κB. At the same time, after the cells were treated with wortmannin, immunoprecipitation and Western Blot were used to detect the expression changes of PARP and NF-κB, finding that wortmannin can inhibit Notchl protective function on PARP and NF-κB. Those results indicate that Notchl inhibit cell apoptosis mediated by PARP and NF-κB under high glucose through Akt pathway.
This research was mainly to explore the pathological mechanism of diabetic retinopathy and detect related factors using animal model in vivo and cell model in vitro. Our study illustrates that high glucose can activate PARP in HRVEC and then activate NF-κB which then activate caspase-3, and Notchl dephosphorylated Akt regulating PARP and NF-κB, further clarifies mechanism of diabetic retinopathy. It provides a good experimental basis and theoretical basis to further study the pathogenesis of diabetic retinopathy, and also provides a new direction and possibilities for the treatment of diabetic retinopathy.
引文
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