Transcriptome profile analysis and validation of differential gene expression of retinal Müller cells stimulated by connective tissue growth factor_Chinese Journal of Ocular Fundus Diseases

Authors：

Bu Shaochong , Zhang Zhe , Wang Qiong , Hong Yaru , Li Xiaorong ,  Dong Lijie

Tianjin Key Laboratory of Retinal Functions and Diseases,Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Dong Lijie, Email: aitaomubang@126.com

Keywords：

Connective tissue growth factor; Transcriptome; Bone morphogenetic protein 4; Müller cell

DOI：

10.3760/cma.j.cn511434-20200116-00026

Video：

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Objective To study the effects of connective tissue growth factor (CTGF) on retinal Müller cells based on transcriptome analysis of RNA-seq technology.Methods Retinal Müller cells were divided into the control group and the CTGF treatment group which was continuously cultured with 10 ng/ml of CTGF for 24 h. The influence of CTGF on the migration of Müller cells were tested by scratching experiments. The RNA transcriptome analysis was applied to complete transcriptome sequencing, differentially expressed genes and functional enrichment analysis of the two groups of cells. HiSeq sequencing technology was used to sequence the whole transcriptome of the two groups of cells to obtain biological big data, and analyze the differentially expressed miRNAs on this basis. The functions and signal pathways of differential miRNAs were analyzed through gene annotation (GO) functional significance enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway significant enrichment analysis. Based on transcriptome data, genes with differential expression multiples in the top ten between the two groups were screened out, and the expression of bone morphogenetic protein 4 (BMP4) gene was verified by real time fluorescence quantification PCR (qRT-PCR), immunofluorescence and Western blot.Results After CTGF stimulation of Müller cells, cell viability and mobility which compared with the control group were significantly increased, with statistically significant differences (t=3.453, P＜0.05). The differential gene expression profile of CTGF induced Müller cells was obtained by RNA transcriptome analysis. Comparing the sequencing results of the two groups, it was found that 325 differentially expressed genes included 152 up-regulated genes and 173 down-regulated genes. The results of GO functional significance enrichment analysis showed that the functions of differential miRNA were mainly divided into three categories: biological processes, cellular components, and molecular functions. These differentially expressed genes were involved in signaling between nervous systems, adhesion between cells, and the interaction between cytokines and their receptors. These differentially expressed genes were involved in different metabolic pathways and biological processes such as tissue inflammation and fibrosis. BMP4 gene was seected for verification through immunofluorescence, qRT-PCR and western blot. The results showed that the expression of BMP4 was significantly higher than that in the control group, and the difference was statistically significant (t=39.490, 10.110, 5.470; P=0.004, 0.001, 0.006).Conclusion CTGF promotes cell proliferation and migration by up-regulating the expression of BMP4 in Müller cells, leading to tissue fibrosis and inducing inflammation.

Citation： Bu Shaochong, Zhang Zhe, Wang Qiong, Hong Yaru, Li Xiaorong, Dong Lijie. Transcriptome profile analysis and validation of differential gene expression of retinal Müller cells stimulated by connective tissue growth factor. Chinese Journal of Ocular Fundus Diseases, 2020, 36(12): 964-970. doi: 10.3760/cma.j.cn511434-20200116-00026 Copy

1.	Pennock S, Haddock LJ, Eliott D, et al. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy?[J]. Prog Retin Eye Res, 2014, 40: 16-34. DOI: 10.1016/j.preteyeres.2013.12.006.
2.	Bu SC, Kuijer R, van der Worp RJ, et al. Glial cells and collagens in epiretinal membranes associated with idiopathic macular holes[J]. Retina, 2014, 34(5): 897-906. DOI: 10.1097/IAE.0000000000000013.
3.	Bu SC, Kuijer R, van der Worp RJ, et al. Immunohistochemical evaluation of idiopathic epiretinal membranes and in vitro studies on the effect of TGF-β on Mülle cells[J]. Invest Ophthalmol Vis Sci, 2015, 56(11): 6506-6514. DOI: 10.1167/iovs.14-15971.
4.	田芳, 胡博杰, 李文博, 等. 高表达多聚嘧啶序列结合蛋白相关剪接因子对糖基化终产物诱导下视网膜Müller细胞凋亡的影响[J]. 中华眼底病杂志, 2019, 35(1): 70-75. DOI: 10.3760/cma.j.issn.1005-1015.2019.01.015.Tian F, Hu BJ, Li WB, et al. Effects of polypyramidine tract binding protein-associated splicing factor overexpression on apoptosis of human Müller cells under advanced glycation end products treatment[J]. Chin J Ocul Fundus Dis, 2019, 35(1): 70-75. DOI: 10.3760/cma.j.issn.1005-1015.2019.01.015.
5.	Xing X, Huang L, Lv Y, et al. DL-3-n-butylphthalide protected retinal Müller cells dysfunction from oxidative stress[J]. Curr Eye Res, 2019, 44(10): 1112-1120. DOI: 10.1080/02713683.2019.1624777.
6.	牛瑞, 东莉洁, 马腾, 等. 结缔组织生长因子重组干扰载体慢病毒颗粒的构建及其对视网膜血管内皮细胞内源性结缔组织生长因子表达的抑制作用[J]. 中华眼底病杂志, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.Niu R, Dong LJ, Ma T, et al. Construction of connective tissue growth factor recombinant interference vector lentiviral particle and its inhibitory effect on endogenous connective tissue growth factor expression in retinal vascular endothelial cells[J]. Chin J Ocul Fundus Dis, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.
7.	Wang Q, Usinger W, Nichols B, et al. Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease[J/OL]. Fibrogenesis Tissue Repair, 2011, 4(1): 4[2011-02-01]. https://fibrogenesis.biomedcentral.com/articles/10.1186/1755-1536-4-4. DOI: 10.1186/1755-1536-4-4.
8.	刘爱华, 高美子, 黄亮瑜, 等. 叉头框转录因子F2小发夹RNA对人眼小梁网细胞外基质蛋白表达的抑制作用[J]. 中华实验眼科杂志, 2019, 37(6): 405-410. DOI: 10.3760/cma.j.issn.2095-0160.2019.06.002.Liu AH, Gao MZ, Huang LY, et al. The inhibitory effect of FoxF2 shRNA on the expression of extracellular matrix of human trabecular meshwork[J]. Chin J Exp Ophthalmol, 2019, 37(6): 405-410. DOI: 10.3760/cma.j.issn.2095-0160.2019.06.002.
9.	王礼明, 东莉洁, 刘勋, 等. 急性原发闭角型青光眼急性发作期房水蛋白质组学分析[J]. 中华眼科杂志, 2019, 55(9): 687-694. DOI: 10.3760/cma.j.issn.0412-4081.2019.09.011.Wang LM, Dong LJ, Liu X, et al. Proteomic analysis of aqueous humor in acute primary angle closure glaucoma[J]. Chin J Ophthalmol, 2019, 55(9): 687-694. DOI: 10.3760/cma.j.issn.0412-4081.2019.09.011.
10.	温德佳, 东莉洁, 李筱荣, 等. iTRAQ蛋白组技术筛选增生性糖尿病视网膜病变防治靶点的研究[J]. 中华眼科杂志, 2019, 55(10): 769-776. DOI: 10.3760/cma.j.issn.0412-4081.2019.10.008.Wen DJ, Dong LJ, Li XR, et al. New exploration of treatment target for proliferative diabetic retinopathy based on iTRAQ LC-MS/MS proteomics[J]. Chin J Ophthalmol, 2019, 55(10): 769-776. DOI: 10.3760/cma.j.issn.0412-4081.2019.10.008.
11.	高美子, 黄亮瑜, 东莉洁, 等. Krüppel样因子6对于TGF-β1诱导的晶状体上皮细胞纤维化的调控作用研究[J]. 中国中医眼科杂志, 2018, 28(1): 4-11. DOI: 10.13444/j.cnki.zgzyykzz.2018.01.002.Gao MZ, Huang LY, Dong LJ, et al. Regulation of Krüppel-like factor 6 on TGF-β1-induced fibrosis of lens epithelial cells[J]. Chinese Journal of Chinese Ophthalmology, 2018, 28(1): 4-11. DOI: 10.13444/j.cnki.zgzyykzz.2018.01.002.
12.	张哲, 刘巨平, 东莉洁, 等. 高糖状态下视网膜血管内皮细胞基因表达谱的RNA-Seq分析[J]. 中华眼底病杂志, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.Zhang Z, Liu JP, Dong LJ, et al. RNA-Seq analysis of gene expression profiling in retinal vascular endothelial cells under high glucose condition[J]. Chin J Ocul Fundus Dis, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.
13.	Dong L, Nian H, Shao Y, et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy[J]. Cell Tissue Res, 2015, 60(2): 233-243. DOI: 10.1007/s00441-014-2104-5.
14.	Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina[J]. Progr Retinal Eye Res, 2006, 25(4): 397-424. DOI: 10.1016/j.preteyeres.2006.05.003.
15.	Eastlake K, Banerjee PJ, Angbohang A, et al. Müller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy[J]. Glia, 2016, 64(4): 495-506. DOI: 10.1002/glia.22942.
16.	Graca AB, Hippert C, Pearson RA. Müller glia reactivity and development of gliosis in response to pathological conditions[J]. Adv Exp Med Biol, 2018, 1074: 303-308. DOI: 10.1007/978-3-319-75402-4_37.
17.	Charteris DG. Proliferative vitreoretinopathy: revised concepts of pathogenesis and adjunctive treatment[J]. Eye (Lond), 2020, 34(2): 241-245. DOI: 10.1038/s41433-019-0699-1.
18.	Cummins TD, Barati MT, Coventry SC, et al. Quantitative mass spectrometry of diabetic kidney tubules identifies GRAP as a novel regulator of TGF-beta signaling[J]. Biochim Biophys Acta, 2010, 1804(4): 653-661. DOI: 10.1016/j.bbapap.2009.09.029.
19.	Tian F, Dong L, Zhou Y, et al. Rapamycin-induced apoptosis in HGF-stimulated lens epithelial cells by AKT/mTOR, ERK and JAK2/STAT3 pathways[J]. Int J Mol Sci, 2014, 15(8): 13833-13848. DOI: 10.3390/ijms150813833.
20.	Dong L, Zhang X, Fu X, et al. PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated Ig epsilon gene transcription by recruitment of HDAC1[J]. J Biol Chem, 2011, 286(5): 3451-3459. DOI: 10.1074/jbc.M110.168377.
21.	Lu M, Wang C, Chen W, et al. MiR-654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPK signaling[J]. DNA Cell Biol, 2018, 37(4): 381-388. DOI: 10.1089/dna.2017.4095.
22.	Eric NK, Maja T, Cosmin V, et al. Non-invasive diagnosis of liver fibrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data meta-analysis[J]. Lancet Gastroenterol Hepatol, 2018, 3(9): 614-625. DOI: 10.1016/S2468-1253(18)30124-9.
23.	Moysidis SN, Thanos A, Vavvas DG. Mechanisms of inflammation in proliferative vitreoretinopathy: from bench to bedside[J/OL]. Mediators Inflamm, 2012, 2012: 815937[2012-09-25]. https://pubmed.ncbi.nlm.nih.gov/23049173/. DOI: 10.1155/2012/815937.
24.	Tikhonovich MV, Iojleva EJ, Gavrilova SA. The role of inflammation in the development of proliferative vitreoretinopathy[J]. Klin Med (Mosk), 2015, 93(7): 14-20.
25.	Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction[J]. J Biochem, 2010, 147(1): 35-51. DOI: 10.1093/jb/mvp148:10.1093/jb/mvp148.
26.	Cheng KH, Ponte JF, Thiagalingam S. Elucidation of epigenetic inactivation of SMAD8 in cancer using targeted expressed gene display[J]. Cancer Res, 2004, 64(5): 1639-1646. DOI: 10.1158/0008-5472.can-03-2688.
27.	Katakawa Y, Funaba M, Murakami M. Smad8/9 is regulated through the BMP pathway[J]. J Cell Biochem, 2016, 117(8): 1788-1796. DOI: 10.1002/jcb.25478.
28.	Yao H, Li H, Yang S, et al. Inhibitory effect of bone morphogenetic protein 4 in retinal pigment epithelial-mesenchymal transition[J/OL]. Sci Rep, 2016, 6: 32182[2016-09-02]. https://pubmed.ncbi.nlm.nih.gov/27586653/. DOI: 10.1038/srep32182.
29.	邢小丽, 黄亮瑜, 东莉洁, 等. 丁基苯酞对H2O2诱导下视网膜色素上皮细胞凋亡的保护作用[J]. 中华眼底病杂志, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.Xing XL, Huang LY, Dong LJ, et al. Effects of butylphthalide on hydrogen peroxide induced retinal pigment epithelial cells injury[J]. Chin J Ocul Fundus Dis, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.
30.	Zhu D, Wu J, Spee C, et al. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration[J]. J Biol Chem, 2009, 284(14): 9529-9539. DOI: 10.1074/jbc.M809393200.
31.	Lau YS, Tian XY, Mustafa MR, et al. Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin Ⅱ-mediated BMP4-oxidative stress cascade[J]. Br J Pharmacol, 2013, 170(6): 1190-1198. DOI: 10.1111/bph.12350.
32.	Tian XY, Lai HY, Wong WT, et al. Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway[J]. J Mol Cell Cardiol, 2012, 52(1): 237-244. DOI: 10.1016/j.yjmcc.2011.10.013.

1. Pennock S, Haddock LJ, Eliott D, et al. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy?[J]. Prog Retin Eye Res, 2014, 40: 16-34. DOI: 10.1016/j.preteyeres.2013.12.006.
2. Bu SC, Kuijer R, van der Worp RJ, et al. Glial cells and collagens in epiretinal membranes associated with idiopathic macular holes[J]. Retina, 2014, 34(5): 897-906. DOI: 10.1097/IAE.0000000000000013.
3. Bu SC, Kuijer R, van der Worp RJ, et al. Immunohistochemical evaluation of idiopathic epiretinal membranes and in vitro studies on the effect of TGF-β on Mülle cells[J]. Invest Ophthalmol Vis Sci, 2015, 56(11): 6506-6514. DOI: 10.1167/iovs.14-15971.
4. 田芳, 胡博杰, 李文博, 等. 高表达多聚嘧啶序列结合蛋白相关剪接因子对糖基化终产物诱导下视网膜Müller细胞凋亡的影响[J]. 中华眼底病杂志, 2019, 35(1): 70-75. DOI: 10.3760/cma.j.issn.1005-1015.2019.01.015.Tian F, Hu BJ, Li WB, et al. Effects of polypyramidine tract binding protein-associated splicing factor overexpression on apoptosis of human Müller cells under advanced glycation end products treatment[J]. Chin J Ocul Fundus Dis, 2019, 35(1): 70-75. DOI: 10.3760/cma.j.issn.1005-1015.2019.01.015.
5. Xing X, Huang L, Lv Y, et al. DL-3-n-butylphthalide protected retinal Müller cells dysfunction from oxidative stress[J]. Curr Eye Res, 2019, 44(10): 1112-1120. DOI: 10.1080/02713683.2019.1624777.
6. 牛瑞, 东莉洁, 马腾, 等. 结缔组织生长因子重组干扰载体慢病毒颗粒的构建及其对视网膜血管内皮细胞内源性结缔组织生长因子表达的抑制作用[J]. 中华眼底病杂志, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.Niu R, Dong LJ, Ma T, et al. Construction of connective tissue growth factor recombinant interference vector lentiviral particle and its inhibitory effect on endogenous connective tissue growth factor expression in retinal vascular endothelial cells[J]. Chin J Ocul Fundus Dis, 2018, 34(6): 580-585. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.011.
7. Wang Q, Usinger W, Nichols B, et al. Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease[J/OL]. Fibrogenesis Tissue Repair, 2011, 4(1): 4[2011-02-01]. https://fibrogenesis.biomedcentral.com/articles/10.1186/1755-1536-4-4. DOI: 10.1186/1755-1536-4-4.
8. 刘爱华, 高美子, 黄亮瑜, 等. 叉头框转录因子F2小发夹RNA对人眼小梁网细胞外基质蛋白表达的抑制作用[J]. 中华实验眼科杂志, 2019, 37(6): 405-410. DOI: 10.3760/cma.j.issn.2095-0160.2019.06.002.Liu AH, Gao MZ, Huang LY, et al. The inhibitory effect of FoxF2 shRNA on the expression of extracellular matrix of human trabecular meshwork[J]. Chin J Exp Ophthalmol, 2019, 37(6): 405-410. DOI: 10.3760/cma.j.issn.2095-0160.2019.06.002.
9. 王礼明, 东莉洁, 刘勋, 等. 急性原发闭角型青光眼急性发作期房水蛋白质组学分析[J]. 中华眼科杂志, 2019, 55(9): 687-694. DOI: 10.3760/cma.j.issn.0412-4081.2019.09.011.Wang LM, Dong LJ, Liu X, et al. Proteomic analysis of aqueous humor in acute primary angle closure glaucoma[J]. Chin J Ophthalmol, 2019, 55(9): 687-694. DOI: 10.3760/cma.j.issn.0412-4081.2019.09.011.
10. 温德佳, 东莉洁, 李筱荣, 等. iTRAQ蛋白组技术筛选增生性糖尿病视网膜病变防治靶点的研究[J]. 中华眼科杂志, 2019, 55(10): 769-776. DOI: 10.3760/cma.j.issn.0412-4081.2019.10.008.Wen DJ, Dong LJ, Li XR, et al. New exploration of treatment target for proliferative diabetic retinopathy based on iTRAQ LC-MS/MS proteomics[J]. Chin J Ophthalmol, 2019, 55(10): 769-776. DOI: 10.3760/cma.j.issn.0412-4081.2019.10.008.
11. 高美子, 黄亮瑜, 东莉洁, 等. Krüppel样因子6对于TGF-β1诱导的晶状体上皮细胞纤维化的调控作用研究[J]. 中国中医眼科杂志, 2018, 28(1): 4-11. DOI: 10.13444/j.cnki.zgzyykzz.2018.01.002.Gao MZ, Huang LY, Dong LJ, et al. Regulation of Krüppel-like factor 6 on TGF-β1-induced fibrosis of lens epithelial cells[J]. Chinese Journal of Chinese Ophthalmology, 2018, 28(1): 4-11. DOI: 10.13444/j.cnki.zgzyykzz.2018.01.002.
12. 张哲, 刘巨平, 东莉洁, 等. 高糖状态下视网膜血管内皮细胞基因表达谱的RNA-Seq分析[J]. 中华眼底病杂志, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.Zhang Z, Liu JP, Dong LJ, et al. RNA-Seq analysis of gene expression profiling in retinal vascular endothelial cells under high glucose condition[J]. Chin J Ocul Fundus Dis, 2018, 34(4): 377-381. DOI: 10.3760/cma.j.issn.1005-1015.2018.04.014.
13. Dong L, Nian H, Shao Y, et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy[J]. Cell Tissue Res, 2015, 60(2): 233-243. DOI: 10.1007/s00441-014-2104-5.
14. Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina[J]. Progr Retinal Eye Res, 2006, 25(4): 397-424. DOI: 10.1016/j.preteyeres.2006.05.003.
15. Eastlake K, Banerjee PJ, Angbohang A, et al. Müller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy[J]. Glia, 2016, 64(4): 495-506. DOI: 10.1002/glia.22942.
16. Graca AB, Hippert C, Pearson RA. Müller glia reactivity and development of gliosis in response to pathological conditions[J]. Adv Exp Med Biol, 2018, 1074: 303-308. DOI: 10.1007/978-3-319-75402-4_37.
17. Charteris DG. Proliferative vitreoretinopathy: revised concepts of pathogenesis and adjunctive treatment[J]. Eye (Lond), 2020, 34(2): 241-245. DOI: 10.1038/s41433-019-0699-1.
18. Cummins TD, Barati MT, Coventry SC, et al. Quantitative mass spectrometry of diabetic kidney tubules identifies GRAP as a novel regulator of TGF-beta signaling[J]. Biochim Biophys Acta, 2010, 1804(4): 653-661. DOI: 10.1016/j.bbapap.2009.09.029.
19. Tian F, Dong L, Zhou Y, et al. Rapamycin-induced apoptosis in HGF-stimulated lens epithelial cells by AKT/mTOR, ERK and JAK2/STAT3 pathways[J]. Int J Mol Sci, 2014, 15(8): 13833-13848. DOI: 10.3390/ijms150813833.
20. Dong L, Zhang X, Fu X, et al. PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated Ig epsilon gene transcription by recruitment of HDAC1[J]. J Biol Chem, 2011, 286(5): 3451-3459. DOI: 10.1074/jbc.M110.168377.
21. Lu M, Wang C, Chen W, et al. MiR-654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPK signaling[J]. DNA Cell Biol, 2018, 37(4): 381-388. DOI: 10.1089/dna.2017.4095.
22. Eric NK, Maja T, Cosmin V, et al. Non-invasive diagnosis of liver fibrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data meta-analysis[J]. Lancet Gastroenterol Hepatol, 2018, 3(9): 614-625. DOI: 10.1016/S2468-1253(18)30124-9.
23. Moysidis SN, Thanos A, Vavvas DG. Mechanisms of inflammation in proliferative vitreoretinopathy: from bench to bedside[J/OL]. Mediators Inflamm, 2012, 2012: 815937[2012-09-25]. https://pubmed.ncbi.nlm.nih.gov/23049173/. DOI: 10.1155/2012/815937.
24. Tikhonovich MV, Iojleva EJ, Gavrilova SA. The role of inflammation in the development of proliferative vitreoretinopathy[J]. Klin Med (Mosk), 2015, 93(7): 14-20.
25. Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction[J]. J Biochem, 2010, 147(1): 35-51. DOI: 10.1093/jb/mvp148:10.1093/jb/mvp148.
26. Cheng KH, Ponte JF, Thiagalingam S. Elucidation of epigenetic inactivation of SMAD8 in cancer using targeted expressed gene display[J]. Cancer Res, 2004, 64(5): 1639-1646. DOI: 10.1158/0008-5472.can-03-2688.
27. Katakawa Y, Funaba M, Murakami M. Smad8/9 is regulated through the BMP pathway[J]. J Cell Biochem, 2016, 117(8): 1788-1796. DOI: 10.1002/jcb.25478.
28. Yao H, Li H, Yang S, et al. Inhibitory effect of bone morphogenetic protein 4 in retinal pigment epithelial-mesenchymal transition[J/OL]. Sci Rep, 2016, 6: 32182[2016-09-02]. https://pubmed.ncbi.nlm.nih.gov/27586653/. DOI: 10.1038/srep32182.
29. 邢小丽, 黄亮瑜, 东莉洁, 等. 丁基苯酞对H2O2诱导下视网膜色素上皮细胞凋亡的保护作用[J]. 中华眼底病杂志, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.Xing XL, Huang LY, Dong LJ, et al. Effects of butylphthalide on hydrogen peroxide induced retinal pigment epithelial cells injury[J]. Chin J Ocul Fundus Dis, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.
30. Zhu D, Wu J, Spee C, et al. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration[J]. J Biol Chem, 2009, 284(14): 9529-9539. DOI: 10.1074/jbc.M809393200.
31. Lau YS, Tian XY, Mustafa MR, et al. Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin Ⅱ-mediated BMP4-oxidative stress cascade[J]. Br J Pharmacol, 2013, 170(6): 1190-1198. DOI: 10.1111/bph.12350.
32. Tian XY, Lai HY, Wong WT, et al. Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway[J]. J Mol Cell Cardiol, 2012, 52(1): 237-244. DOI: 10.1016/j.yjmcc.2011.10.013.

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Transcriptome profile analysis and validation of differential gene expression of retinal Müller cells stimulated by connective tissue growth factor

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