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. 高表達多聚嘧啶序列結合蛋白相關剪接因子對糖基化終產物誘導下視網膜Müller細胞凋亡的影響[J]. 中華眼底病雜志, 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, 東莉潔, 馬騰, 等. 結締組織生長因子重組干擾載體慢病毒顆粒的構建及其對視網膜血管內皮細胞內源性結締組織生長因子表達的抑制作用[J]. 中華眼底病雜志, 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.	劉愛華, 高美子, 黃亮瑜, 等. 叉頭框轉錄因子F2小發夾RNA對人眼小梁網細胞外基質蛋白表達的抑制作用[J]. 中華實驗眼科雜志, 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.	王禮明, 東莉潔, 劉勛, 等. 急性原發閉角型青光眼急性發作期房水蛋白質組學分析[J]. 中華眼科雜志, 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.	溫德佳, 東莉潔, 李筱榮, 等. iTRAQ蛋白組技術篩選增生性糖尿病視網膜病變防治靶點的研究[J]. 中華眼科雜志, 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, 黃亮瑜, 東莉潔, 等. Krüppel樣因子6對于TGF-β1誘導的晶狀體上皮細胞纖維化的調控作用研究[J]. 中國中醫眼科雜志, 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.	張哲, 劉巨平, 東莉潔, 等. 高糖狀態下視網膜血管內皮細胞基因表達譜的RNA-Seq分析[J]. 中華眼底病雜志, 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.	邢小麗, 黃亮瑜, 東莉潔, 等. 丁基苯酞對H2O2誘導下視網膜色素上皮細胞凋亡的保護作用[J]. 中華眼底病雜志, 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. 高表達多聚嘧啶序列結合蛋白相關剪接因子對糖基化終產物誘導下視網膜Müller細胞凋亡的影響[J]. 中華眼底病雜志, 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, 東莉潔, 馬騰, 等. 結締組織生長因子重組干擾載體慢病毒顆粒的構建及其對視網膜血管內皮細胞內源性結締組織生長因子表達的抑制作用[J]. 中華眼底病雜志, 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. 劉愛華, 高美子, 黃亮瑜, 等. 叉頭框轉錄因子F2小發夾RNA對人眼小梁網細胞外基質蛋白表達的抑制作用[J]. 中華實驗眼科雜志, 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. 王禮明, 東莉潔, 劉勛, 等. 急性原發閉角型青光眼急性發作期房水蛋白質組學分析[J]. 中華眼科雜志, 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. 溫德佳, 東莉潔, 李筱榮, 等. iTRAQ蛋白組技術篩選增生性糖尿病視網膜病變防治靶點的研究[J]. 中華眼科雜志, 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, 黃亮瑜, 東莉潔, 等. Krüppel樣因子6對于TGF-β1誘導的晶狀體上皮細胞纖維化的調控作用研究[J]. 中國中醫眼科雜志, 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. 張哲, 劉巨平, 東莉潔, 等. 高糖狀態下視網膜血管內皮細胞基因表達譜的RNA-Seq分析[J]. 中華眼底病雜志, 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. 邢小麗, 黃亮瑜, 東莉潔, 等. 丁基苯酞對H2O2誘導下視網膜色素上皮細胞凋亡的保護作用[J]. 中華眼底病雜志, 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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