血红素氧合酶-1对糖尿病视网膜病变神经元和血管内皮细胞保护作用的研究及其机制探讨
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摘要
目的：HO-1作为一种经典的抗氧化酶具有潜在的抗炎、抗氧化损伤、抗凋亡和抗细胞增殖的作用。Nrf2/ERK介导的HO-1表达在肿瘤和血管性疾病中起到关键作用。本研究旨在探讨HO-1的表达变化在糖尿病视网膜病变中对视网膜神经元和血管内皮细胞的保护作用,并从基因水平和微小RNA水平分析可能的作用机制。
方法：SD大鼠腹腔注射STZ(60mg/kg)造模并监测血糖,hemin (20mg/kg)腹腔注射进行治疗。成模后2周、4周、6周、8周、12周检测大鼠血液Hb和Hb1Ac水平；TUNEL法检测视网膜凋亡的神经节细胞。Western blot和real-time PCR检测视网膜HO-1、HIF-1α、SOD-1、VEGF、p53和bcl-2水平。Western blot法检测Nrf2、tERK1/2和pERK1/2表达。进一步采用免疫荧光法检测视网膜HO-1、Nrf2、pERK和GFAP蛋白的分布。体外培养SD大鼠视网膜原代Muller细胞,分别在正常培养和高糖培养条件下,用HO-1特异性激活剂hemin和特异性阻滞剂ZnPP进行干预,检测Muller细胞HO-1、Nrf-2、SOD-1、bcl-2、HIF-1α和VEGF的表达。hemin/ZnPP干预后的Muller细胞和血管内皮细胞共培养,检测血管内皮细胞VEGF、ZO-1的表达变化。进一步在正常-疾病-治疗模型中筛选差异微小RNA并进行分析。
结果：活体方面,hemin治疗能升高糖尿病大鼠血红蛋白水平,降低糖化血红蛋白水平。hemin能有效诱导糖尿病视网膜高表达HO-1,伴随Nrf2/ERK信号通路的相应变化,以及SOD-1、bcl-2水平的上升和HIF-1α、P53、VEGF水平的下降,进一步激活Muller细胞GFAP的表达。HO-1的高水平对视网膜神经节细胞的凋亡具有保护作用。离体方面,hemin/ZnPP能有效诱导/阻滞Muller细胞HO-1的表达,伴随Nrf2、SOD-1、bcl-2表达的升高和HIF-1α、P53、VEGF表达的降低,进一步增加/减少血管内皮细胞ZO-1水平,减少/增加血管内皮细胞VEGF水平。miR-214和miR-181b是功能和信号通路的关键差异微小RNA。
结论：HO-1通过Nrf2/ERK信号通路,对糖尿病视网膜病变神经元和血管内皮细胞起到保护作用,其抗炎、抗氧化损伤、抗凋亡、抗增殖的作用机制可能与其调控诱导的SOD-1和bcl-2表达以及调控抑制的HIF-1α、P53、VEGF表达相关。Miiller细胞是HO-1诱导激活的主要应答细胞,进一步调控HO-1对视网膜神经元和血管内皮细胞的保护作用。miR-214和miR-181b是糖尿病视网膜病变中HO-1介导的保护作用之关键靶点。
Heme Oxygenase-1Mediated Protection of Neurons and Vascular Endothelial Cells in Diabetic Retinopathy
Objective Heme oxygenase-1(HO-1) is a novel enzyme with potent anti-inflammatory, anti-oxidant and anti-proliferative effects. The expression of HO-1via Nrf2/ERK pathway has been shown to play a key role in some oncoma and hematologic diseases. This research aims to investigate the protective effects of HO-1in streptozotocin(STZ)-induced diabetic rats'retina and vascular endothelial cells. Explore the potential mechanism in both gene level and microRNA level. Methods Sprague-Dawley (SD) rats were induced to diabetes by intraperitoneal injection of STZ (60mg/kg). Later, some of the rats were given intraperitoneal injections of hemin (20mg/kg) to induce expression of HO-1. The protective effects of hemin were evaluated by examining the hemoglobin concentration (Hb) and the glycosylated hemoglobin (HbAlc) level of blood from the rats, including the TUNEL positive retinal ganglion cells (RGCs). We also documented the expressions of HO-1, HIF-1α, SOD-1, VEGF, p53and bcl-2by Western blot analysis and real-time quantitative PCR. Expressions of Nrf2, tERK1/2and pERK1/2were detected only by Western blot analysis. HO-1, Nrf2, pERK and GFAP proteins were detected by immunofluorescence. We also identified hemin/ZnPP-IX as inducer/inhibitor of heme oxygenase-1(HO-1) in muller cells which were isolated from Sprague-Dawley (SD) rats'eyes and cultured in vitro. The expression of HO-1, Nrf-2, HIF-1α, SOD-1and bcl-2were confirmed by real-time PCR, Western immunoblot analysis and immunohistochemistry in Muller cells cultured by DMEM contained high and normal concentrations of glucose. VEGF were detected only by ELISA. HUVECs were co-cultured with muller cells pretreated by hemin and ZnPP-IX and the expression of ZO-1and VEGF were detected. A normal-disease-treatment model for detection of differential gene expression in small microarray experiments was performed in STZ-induced and hemin-treated rat retina. And the multiclass differences were analyzed. Results The Hb level increased in hemin-treated rat blood, while the HbAlc level decreased. Hemin significantly activated HO-1expression in the full retinal layer of diabetic rats, combined with accordant changes of Nrf2/pERK protein expression, and further up-regulated the expression of GFAP in Miiller cells. Retinal ganglion cells displayed greater sensitivity to apoptosis when the HO-1level was lower. Overexpression of HO-1was associated with an increase in the activation of SOD-1and bcl-2, and suppression of the expression of HIF-la, VEGF and p53. hemin/ZnPP-IX significantly increased/blocked HO-1expression combined with accordant changes of Nrf2, HIF-la, VEGF, SOD-1and bcl-2gene expression in Miiller cells and further down-regulated/up-regulated the expression of VEGF, up-regulated/down-regulated the expression of ZO-1in vascular endothelial cells. miR-214and miR-181b were the two key microRNA in the differences of function and pathway. Conclusions HO-1is an important positive modulator of the Nrf2/ERK-dependent signaling that counteracts diabetic retinopathy-mediated injuries in microvascular and retinal neurons, acting through anti-inflammatory, anti-apoptotic and anti-proliferative effects which related to the induction of SOD-1and bcl-2and to the suppression of HIF-la, p53and VEGF. Miiller cell is the cell which response to the regulation of HO-1level and its protection of neurons and vascular endothelial cells in diabetic retinopathy. miR-214and miR-181b may be the new research target for HO-1-mediated protection.
方法：SD大鼠腹腔注射STZ(60mg/kg)造模并监测血糖,hemin (20mg/kg)腹腔注射进行治疗。成模后2周、4周、6周、8周、12周检测大鼠血液Hb和Hb1Ac水平；TUNEL法检测视网膜凋亡的神经节细胞。Western blot和real-time PCR检测视网膜HO-1、HIF-1α、SOD-1、VEGF、p53和bcl-2水平。Western blot法检测Nrf2、tERK1/2和pERK1/2表达。进一步采用免疫荧光法检测视网膜HO-1、Nrf2、pERK和GFAP蛋白的分布。体外培养SD大鼠视网膜原代Muller细胞,分别在正常培养和高糖培养条件下,用HO-1特异性激活剂hemin和特异性阻滞剂ZnPP进行干预,检测Muller细胞HO-1、Nrf-2、SOD-1、bcl-2、HIF-1α和VEGF的表达。hemin/ZnPP干预后的Muller细胞和血管内皮细胞共培养,检测血管内皮细胞VEGF、ZO-1的表达变化。进一步在正常-疾病-治疗模型中筛选差异微小RNA并进行分析。
结果：活体方面,hemin治疗能升高糖尿病大鼠血红蛋白水平,降低糖化血红蛋白水平。hemin能有效诱导糖尿病视网膜高表达HO-1,伴随Nrf2/ERK信号通路的相应变化,以及SOD-1、bcl-2水平的上升和HIF-1α、P53、VEGF水平的下降,进一步激活Muller细胞GFAP的表达。HO-1的高水平对视网膜神经节细胞的凋亡具有保护作用。离体方面,hemin/ZnPP能有效诱导/阻滞Muller细胞HO-1的表达,伴随Nrf2、SOD-1、bcl-2表达的升高和HIF-1α、P53、VEGF表达的降低,进一步增加/减少血管内皮细胞ZO-1水平,减少/增加血管内皮细胞VEGF水平。miR-214和miR-181b是功能和信号通路的关键差异微小RNA。
结论：HO-1通过Nrf2/ERK信号通路,对糖尿病视网膜病变神经元和血管内皮细胞起到保护作用,其抗炎、抗氧化损伤、抗凋亡、抗增殖的作用机制可能与其调控诱导的SOD-1和bcl-2表达以及调控抑制的HIF-1α、P53、VEGF表达相关。Miiller细胞是HO-1诱导激活的主要应答细胞,进一步调控HO-1对视网膜神经元和血管内皮细胞的保护作用。miR-214和miR-181b是糖尿病视网膜病变中HO-1介导的保护作用之关键靶点。
Heme Oxygenase-1Mediated Protection of Neurons and Vascular Endothelial Cells in Diabetic Retinopathy
Objective Heme oxygenase-1(HO-1) is a novel enzyme with potent anti-inflammatory, anti-oxidant and anti-proliferative effects. The expression of HO-1via Nrf2/ERK pathway has been shown to play a key role in some oncoma and hematologic diseases. This research aims to investigate the protective effects of HO-1in streptozotocin(STZ)-induced diabetic rats'retina and vascular endothelial cells. Explore the potential mechanism in both gene level and microRNA level. Methods Sprague-Dawley (SD) rats were induced to diabetes by intraperitoneal injection of STZ (60mg/kg). Later, some of the rats were given intraperitoneal injections of hemin (20mg/kg) to induce expression of HO-1. The protective effects of hemin were evaluated by examining the hemoglobin concentration (Hb) and the glycosylated hemoglobin (HbAlc) level of blood from the rats, including the TUNEL positive retinal ganglion cells (RGCs). We also documented the expressions of HO-1, HIF-1α, SOD-1, VEGF, p53and bcl-2by Western blot analysis and real-time quantitative PCR. Expressions of Nrf2, tERK1/2and pERK1/2were detected only by Western blot analysis. HO-1, Nrf2, pERK and GFAP proteins were detected by immunofluorescence. We also identified hemin/ZnPP-IX as inducer/inhibitor of heme oxygenase-1(HO-1) in muller cells which were isolated from Sprague-Dawley (SD) rats'eyes and cultured in vitro. The expression of HO-1, Nrf-2, HIF-1α, SOD-1and bcl-2were confirmed by real-time PCR, Western immunoblot analysis and immunohistochemistry in Muller cells cultured by DMEM contained high and normal concentrations of glucose. VEGF were detected only by ELISA. HUVECs were co-cultured with muller cells pretreated by hemin and ZnPP-IX and the expression of ZO-1and VEGF were detected. A normal-disease-treatment model for detection of differential gene expression in small microarray experiments was performed in STZ-induced and hemin-treated rat retina. And the multiclass differences were analyzed. Results The Hb level increased in hemin-treated rat blood, while the HbAlc level decreased. Hemin significantly activated HO-1expression in the full retinal layer of diabetic rats, combined with accordant changes of Nrf2/pERK protein expression, and further up-regulated the expression of GFAP in Miiller cells. Retinal ganglion cells displayed greater sensitivity to apoptosis when the HO-1level was lower. Overexpression of HO-1was associated with an increase in the activation of SOD-1and bcl-2, and suppression of the expression of HIF-la, VEGF and p53. hemin/ZnPP-IX significantly increased/blocked HO-1expression combined with accordant changes of Nrf2, HIF-la, VEGF, SOD-1and bcl-2gene expression in Miiller cells and further down-regulated/up-regulated the expression of VEGF, up-regulated/down-regulated the expression of ZO-1in vascular endothelial cells. miR-214and miR-181b were the two key microRNA in the differences of function and pathway. Conclusions HO-1is an important positive modulator of the Nrf2/ERK-dependent signaling that counteracts diabetic retinopathy-mediated injuries in microvascular and retinal neurons, acting through anti-inflammatory, anti-apoptotic and anti-proliferative effects which related to the induction of SOD-1and bcl-2and to the suppression of HIF-la, p53and VEGF. Miiller cell is the cell which response to the regulation of HO-1level and its protection of neurons and vascular endothelial cells in diabetic retinopathy. miR-214and miR-181b may be the new research target for HO-1-mediated protection.
引文
1. Rungger-Brandle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci.2000;41:1971-1980.
2. Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK, LaNoue KF, Norbury CC, Quinn PG, Sandirasegarane L, Simpson IA. JDRF Diabetic Retinopathy Center Group. Diabetic retinopathy:Seeing beyond glucose-induced microvascular disease. Diabetes.2006;55:2401-2411.
3. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1:unleashing the protective properties of heme. Trends Immunol.2003;24:449-455.
4. Soares MP, Bach FH. Heme oxygenase-1:from biology to therapeutic potential. Trends Mol Med.2009;15:50-58.
5. Zhang M, Zhang BH, Chen L, An W. Overexpression of heme oxygenase-1 protects smooth muscle cells against oxidative injury and inhibits cell proliferation. Cell Res.2002;12:123-132.
6. Tamion F, Richard V, Renet S, Thuillez C. Intestinal preconditioning prevents inflammatory response by modulatinghemeoxygenase-1 expression in endotoxic shock model. Am J Physiol Gastrointest Liver Physiol.2007;293:G1308-1314.
7. Choi BM, Kim BR. Upregulation of heme oxygenase-1 by brazilin via the phosphatidylinositol 3-kinase/Akt and ERK pathways and its protective effect against oxidative injury. Eur J Pharmacol.2008;580:12-18.
8. Ndisang JF. Role of heme oxygenase in inflammation, insulin-signalling, diabetes and obesity. Mediators Inflamm.2010;2010:359732.
9. Kruger AL, Peterson SJ, Schwartzman ML, Fusco H, McClung JA, Weiss M, Shenouda S, Goodman AI, Goligorsky MS, Kappas A, Abraham NG. Up-regulation of heme oxygenase provides vascular protection in an animal model of diabetes through its antioxidant and antiapoptotic effects. J Pharmacol Exp Ther.2006;319:1144-1152.
10. Arai-Gaun S, Katai N, Kikuchi T, Kurokawa T, Ohta K, Yoshimura N. Heme oxygenase-1 induced in muller cells plays a protective role in retinal ischemia-reperfusion injury in rats. Invest Ophthalmol Vis Sci. 2004;45:4226-4232.
11. Sun MH, Pang JH, Chen SL, Han WH, Ho TC, Chen KJ, Kao LY, Lin KK, Tsao YP. Retinal protection from acute glaucoma-induced ischemia-reperfusion injury through pharmacologic induction of heme oxygenase-1. Invest Ophthalmol Vis Sci.2010;51:4798-4808.
12. Sun MH, Pang JH, Chen SL, Kuo PC, Chen KJ, Kao LY, Wu JY, Lin KK, Tsao YP. Photoreceptor protection against light damage by AAV-mediated overexpression of heme oxygenase-1. Invest Ophthalmol Vis Sci. 2007;48:5699-5707.
13. Lin JH, Villalon P, Martasek P, Abraham NG. Regulation of heme oxygenase gene expression by cobalt in rat liver and kidney. Eur J Biochem. 1990;192:577-582.
14. Shibahara S, Miiller RM, Taguchi H. Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem.1987;262:12889-12892.
15. Desbuards N, Rochefort GY, Schlecht D, Machet MC, Halimi JM, Eder V, Hyvelin JM, Antier D. Heme oxygenase-1 inducer hemin prevents vascular thrombosis. Thromb Haemost.2007;98:614-620.
16. Morita K, Lee MS, Her S. Possible relation of hemin-induced HO-1 expression to the upregulation of VEGF and BDNF mRNA levels in rat C6 glioma cells. J Mol Neurosci.2009;38:31-40.
17. Zijlstra GS, Brandsma CA, Harpe MF, Van Dam GM, Slebos DJ, Kerstjens HA, De Boer AH, Frijlink HW. Dry powder inhalation of hemin to induce heme oxygenase expression in the lung. Eur J Pharm Biopharm.2007;67:667-675.
18. Nussler AK, Hao L, Knobeloch D, Yao P, Nussler NC, Wang Z, Liu L, Ehnert S. Protective role of HO-1 for alcohol-dependent liver damage. Dig Dis. 2010;28:792-798.
19. Naughton P, Hoque M, Green CJ, Foresti R, Motterlini R. Interaction of heme with nitroxyl or nitric oxide amplifies heme oxygenase-1 induction:involvement of the transcription factor Nrf2. Cell Mol Biol (Noisy-le-grand).2002;48:885-894.
20. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res.2010;690:12-23.
21. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11:497-508.
22. Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys.2004;432:252-260.
23. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, Motterlini R. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J.2003;371:887-895.
24. Steinle JJ, Chin VC, Williams KP, Panjala SR. Beta-adrenergic receptor stimulation modulates iNOS protein levels through p38 and ERK1/2 signaling in human retinal endothelial cells. Exp Eye Res.2008;87:30-34.
25. Ye X, Xu G, Chang Q, Fan J, Sun Z, Qin Y, Jiang AC. ERK1/2 signaling pathways involved in VEGF release in diabetic rat retina. Invest Ophthalmol Vis Sci.2010;51:5226-5233.
26. Cukiernik M, Mukherjee S, Downey D, Chakabarti S. Heme oxygenase in the retina in diabetes. Curr Eye Res.2003;27:301-308.
27. Semenza G.L.,AgAni F.,Booth G., et al. Structural and functional analysis of hypoxia-inducible factor 1.Kidney Int.,1997,5(4) 1:553-555
28. Ozaki H., Yu AY., Della N., et al. Hypoxia inducible factor-lalpha is increased in ischemic retina:temporal and spatial correlation with VEGF expression. Investigative Ophthalmology and Visual Science,1999,40(1):182-189
29. Lukiw W.J.(2003), Ottlecz A., Lambrou G., Grueninger M., Finley J., Thompson H.W., et al. Coordinate activation of HIF-1 and NF-kappaB DNA bing and COX-2 and VEGF expression in retinal cells by hypoxia. Investigative Ophthalmology and Visual Science,4(10):4163-4170
30. Li, Q. F., Dai, A. G. (2004). Hypoxia Inducible factor-1 alpha correlates the expression of heme oxygenase 1 gene in pulmonary arteries of rat with hypoxia-induced pulmonary hypertension. Acta Biochimica et Biophysica Sinica,36(2):133-140
31. Kim B, Tang Q, Biswas PS. Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes. Am J Pathol; 2004; 16 5(5):2177-85
32. Tolentino MJ,Brucker AJ, Fosnot J.Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina; 2004;24(1);132-8.
33. Liu X, Cheng Y, Zhang S, et al. A necessary role of miR-222 and miR-221 in vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res. 2009;104:476-487.
34. Cheng Y, Liu X, Yang J, et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res.2009;105:158-166.
35. Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and anti sense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res.2007 100(11):1579-88.
36. Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol.2002; 12:735-739.
37. Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, Wang Z, Qiu S, Wang X, Yang G, Sun H, Tang Z, Wu Y, Zhu H, Fan J. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol.2011 Dec 20;29(36):4781-8.
38. Kenneth JL, Thomas DS. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-A ACT Method. Meth.2001;25:402-408.
39. Ndisang JF, Jadhav A.Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months.J Card Fail.2009;15:616-628.
40. Wang RQ, Nan YM, Wu WJ, Kong LB, Han F, Zhao SX, Kong L, Yu J. Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. Lipids Health Dis.2011;10:31.
41. Natarajan R, Fisher BJ, Fowler AA 3rd. Hypoxia inducible factor-1 modulates hemin-induced IL-8 secretion in microvascular endothelium. Microvasc Res. 2007;73:163-172.
42. Choi KM, Gibbons SJ, Nguyen TV, Stoltz GJ, Lurken MS, Ordog T, Szurszewski JH, Farrugia G. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology. 2008;135:2055-2064.
43. Fouad AA, Qureshi HA, Al-Sultan AI, Yacoubi MT, Ali AA. Protective effect of hemin against cadmium-induced testicular damage in rats. Toxicology. 2009;257:153-160.
44. Mazure NM, Brahimi-Horn MC, Berta MA, Benizri E, Bilton RL, Dayan F, Ginouves A, Berra E, Pouyssegur J. HIF-1:master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol.2004;68:971-980.
45. Ambati J, Chalam KV, Chawla DK, D'Angio CT, Guillet EG, Rose SJ, Vanderlinde RE, Ambati BK. Elevated gamma aminobutyricacid, glutamate, and vascular endothelial growth factor levelsin the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol.1997; 115:1161-1166.
46. Hofseth LJ, Hussain SP, Harris CC. p53:25 years after its discovery. Trends Pharmacol. Sci.2004;25:177-181.
47. Wang X, Ye XL, Liu R, Chen HL, Bai H, Liang X, Zhang XD, Wang Z, Li WL, Hai CX. Antioxidant activities of oleanolic acid in vitro:possible role of Nrf2 and MAP kinases. Chem Biol Interact.2010;184:328-337.
48. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A. Miiller cells in the healthy and diseased retina. Prog Retin Eye Res.2006;25:397-424.
49. de Melo Reis RA, Ventura AL, Schitine CS, de Mello MC, de Mello FG. Miiller glia as an active compartment modulating nervous activity in the vertebrate retina: neurotransmitters and trophic factors. Neurochem Res.2008;33:1466-1474.
50. Liu W, Xu GZ, Jiang CH, Da CD. Expression of macrophage colony-stimulating factor (M-CSF) and its receptor in streptozotocin-induced diabetic rats. Curr Eye Res.2009;34:123-133.
51. Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Exp Diabetes Res.2007;2007:43603.
52. Valdivia A, Perez-Alvarez S, Aroca-Aguilar JD, Ikuta I, Jordan J. Superoxide dismutases:a physiopharmacological update. J Physiol Biochem. 2009;65:195-208.
53. Turan B. Role of antioxidants in redox regulation of diabetic cardiovascular complications. Curr Pharm Biotechnol.2010;11:819-836.
54. Du Y, Miller CM, Kern TS. Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med.2003;35:1491-1499.
55. Craven PA, Melhem MF, Phillips SL, DeRubertis FR. Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. Diabetes.2001;50:2114-2125.
56. DeRubertis FR, Craven PA, Melhem MF, Salah EM. Attenuation of renal injury in db/db mice overexpressing superoxide dismutase:evidence for reduced superoxide-nitric oxide interaction. Diabetes.2004;53:762-768.
57. Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia:implications for diabetic retinopathy. Diabetes. 2004;53:2931-2938.
58. Arden GB, Sivaprasad S. Hypoxia and Oxidative Stress in the Causation of Diabetic Retinopathy. Curr Diabetes Rev.2011 Sep 15. [Epub ahead of print]
59. Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS. Hypoxia-inducible factor 1 alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol.2003;23:359-369.
60. Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA. Hypoxia inducible factor-1 alpha is increased in ischemic retina:temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci.1999;40:182-189.
61. Schmid T, Zhou J, Brune B. HIF-1 and p53:communication of transcription factors under hypoxia. J Cell Mol Med.2004;8:423-431.
62. Lin M, Chen Y, Jin J, Hu Y, Zhou KK, Zhu M, Le YZ, Ge J, Johnson RS, Ma JX. Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Muller cells. Diabetologia.2011;54:1554-1566.
63. Nakamura M, Kanamori A, Negi A. Diabetes mellitus as a risk factor for glaucomatous optic neuropathy. Ophthalmologica.2005;219:1-10.
64. van Dijk HW, Verbraak FD, Kok PH, Garvin MK, Sonka M, Lee K, Devries JH, Michels RP, van Velthoven ME, Schlingemann RO, Abramoff MD. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest Ophthalmol Vis Sci.2010;51:3660-3665.
65. Panahian N, Yoshiura M, Maines MD. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J Neurochem.1999;72:1187-1203.
66. Adamis AP, Miller JW, Bernal MT, D'Amico DJ, Folkman J, Yeo TK, Yeo KT. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol.1994;118:445-450.
67. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA.1995;92:10457-10461.
68. Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29:789-791.
69. Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP. Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol. 2002;160:501-509.
70. Yu DY, Cringle SJ, Su EN, Yu PK, Jerums G, Cooper ME. Pathogenesis and intervention strategies in diabetic retinopathy. Clin Experiment Ophthalmol. 2001;29:164-166.
71. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327-1334.
72. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(Suppl.1):S62-S69.
73. Wright, G.W. and R.M. Simon. A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003;19:2448-2455.
74. Yang, H., N. Crawford, L. Lukes, R. Finney, M. Lancaster, and K.W. Hunter. Metastasis predictive signature profiles pre-exist in normal tissues. Clin Exp Metastasis 2005;22:593-603.
75. Clarke, R., H.W. Ressom, A. Wang, J. Xuan, M.C. Liu, E.A. Gehan, and Y. Wang. The properties of high-dimensional data spaces:implications for exploring gene and protein expression data. Nat Rev Cancer.2008; 8:37-49.
76. Ramoni, M.F., P. Sebastiani, and I.S. Kohane. Cluster analysis of gene expression dynamics. Proc Natl Acad Sci USA.2002; 99:9121-9126.
77. Miller, L.D., P.M. Long, L. Wong, S. Mukherjee, L.M. McShane, and E.T. Liu. Optimal gene expression analysis by microarrays. Cancer Cell.2002; 2:353-361.
78. Yi, M., J.D. Horton, J.C. Cohen, H.H. Hobbs, and R.M. Stephens. WholePathwayScope:a comprehensive pathway-based analysis tool for high-throughput data. BMC Bioinformatics.2006;7:30.
79. Je-Gun, J, Kyu-Baek, H, Jin-Wu, N, Soo-Jin, K, and Byoung-Tak, Z. Discovery of microRNA-mRNA modules via population-based probabilistic learning. Bioinfo.2007;23:1141.
80. Reut, S, Daniel, L, Moshe, Oren, Yitzhak, P. Global and local architecture of the mammalian microRNA-transcription factor regulatory network. PLOS One.2007; 3:1291
81.Bartel DP. Micro RNAs:genomics, biogenesis, mechanism and function. Cell.2004;116(2):281-297.
82.Poy MN, Eliasson L, Krutzfeidt J, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature.2004;432(7014):226-230.
83.Plaisance V, Abderrahmani A, Perret-Menoud V et al. MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. JBiol Chem.2006;281(37):26932-42.
84.He A, Zhu L, Gupta N, et al. Over-expression of miR-29, highly upregulated in diabetic rats, leads to insulin resistance in 3T3-LI adipocytes. Mol Endocrinol. 2007;21(11):2785-94.
85.Xiao J, Luo X, Lin H, et al. MicroRNA miR-133 represses HERG K+channel expression contributing to QT prolongation in diabetic heans. J Biol Chem. 2007;282(17):12363-7.
86. Duan Q, Wang X, Gong W, Ni L, Chen C, He X, Chen F, Yang L, Wang P, Wang DW. ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS One.2012;7(2):e31518.
87. Schwarzenbach H, Milde-Langosch K, Steinbach B, Muller V, Pantel K. Diagnostic potential of PTEN-targeting miR-214 in the blood of breast cancer patients. Breast Cancer Res Treat.2012 Feb 19. [Epub ahead of print]
88. Peng RQ, Wan HY, Li HF, Liu M, Li X, Tang H. MicroRNA-214 Suppresses The Growth and Invasiveness of Cervical Cancer Cells by Targeting UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 7. J Biol Chem.2012 Mar 7. [Epub ahead of print]
89. Chen YQ, Wang XX, Yao XM, Zhang DL, Yang XF, Tian SF, Wang NS. Abated microRNA-195 expression protected mesangial cells from apoptosis in early diabetic renal injury in mice. J Nephrol.2011 Oct 4:0. doi:10.5301/jn.5000034. [Epub ahead of print]
90. Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ, Seals DR. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol.2012;47(1):45-51.
91. Aurora AB, Mahmoud AI, Luo X, Johnson BA, van Rooij E, Matsuzaki S, Humphries KM, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. J Clin Invest.2012;122(4):1222-32.
92. van Mil A, Grundmann S, Goumans MJ, Lei Z, Oerlemans MI, Jaksani S, Doevendans PA, Sluijter JP. MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release. Cardiovasc Res. 2012;93(4):655-65.
93. Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X. MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol. 2012;227(2):772-83.
94. Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-kappaB signaling. JMol Cell Biol.2011;3(3):159-66.
95. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell.2010;39(4):493-506.
96. Zhao J, Gong AY, Zhou R, Liu J, Eischeid AN, Chen XM. Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-a-induced transcription of proinflammatory genes in liver epithelial cells.J Immunol. 2012;188(3):1266-74.
97. Visone R, Veronese A, Balatti V, Croce CM. MiR-181b:new perspective to evaluate disease progression in chronic lymphocytic leukemia. Oncotarget. 2012;3(2):195-202.
98. Visone R, Veronese A, Rassenti LZ, Balatti V, Pearl DK, Acunzo M, Volinia S, Taccioli C, Kipps TJ, Croce CM. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood.2011;118(11):3072-9.
[1]John E Dowling.Retina.1987,7-9.
[2]Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells[J]. Vision Res,1997,37(24):3483.
[3]Dreher Z, Robinson SR, Distler C. Muller cells in vascular and avascular retina:a survey of seven mammals[J].J Comp Neur,1992,23:59-80
[4]Schwartz EA, Tachibana M. Electrophysiology of glutamate and sodium co-transport in a glial cell of the salamander retina[J].J Physiol,1990,426:43-80
[5]Newman EA. Acid efflux from retinal glial cells generated by sodium bicarbonate cotransport[J]. J Neurosci,1996,16:159-168
[6]Reichelt W, Hernandez M, Damian RT, et al. Damian RT GABAA receptor currents recorded from Muller glial cells of the baboon (Papiocynocephalus) retina[J].Neurosci Lett,1996,203:159-162
[7]Kim LB,Kim KY,Joo CK,et al.Reaction of Muller cells after increased intraocular pressure in the rat retina[J].Exp Brain Res,1998,121:419-424
[8]Napper GA, Pianta MJ, Kalloniatis M.Reduced glutamate uptake by retinal glial cells under ischemic/hypoxic condition[J].Vis Neurosci,1999,16(1):149
[9]Napper GA, Kalloniatis M. Neurochemical changes following postmortem ischemia in the rat retina[J].Vis Neurosci,1999,16(6):1169
[10]Winkler BS, Arnold MJ, Brassell MA, el al. Energy metabolism in human retinal Muller cells[J]. Invest Ophtholmol Vis, Sci,2000,41(10):3183
[11]Harada T, Harada C, Watanabe M, et al. Functions of the two glutamate transporter, GLAST and GLT-1 in the retina[J].ProcNatl Acad Sci USA,1998, 95(8):4663
[12]Huster D, Reichenbach A, Reichelt W. The glutathione content of retinal Muller cells:effect of pathological conditions[J].N eurothem Int,2000,36(4-5):461
[13]Gohdo T, Ueda H, Ohno S, et al.Ophthalmic Res,2001,33(5):298
[14]Akiyama H,Nakazawa T,Shimura M,et al.Neuroreport,2002,13:2103
[15]Bignami A, Dahl D,Exp Eye Res,1979,28(1):63
[16]Chu Y, Humphrey MF, Alder W,et al.Immunocytochemical localization of basic fibroblast growth factor and glial fibrillary acidic protein after laser photocoagulation in the Royl college surgeons rat. Aust NZ J Ophthalmol,1998;26(1):87
[17]Chen H,Weber AJ.Glia,2002,38(2):115
[18]Barber AJ, Antonetti DA, Gardner TW.Altered expression of retinal occluding and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group.Invest Ophthalmol Vis Sci,2000;41:3561-3568
[19]I.i Q, Zemel E, Miller B, et al. Exp Eye Res,2002.74(5):615
[20]Lieth E,Barber AJ,Xu B,et al. Diabetes,1998,47(5):815
[21]Ishikawa A, Ishiguro S, Tamai M. Changes in GAB A metabolism in streptozotoc induced diabetic rat retinas. Curr Eye Res,1996; 15:63-71
[22]Sueishi K, Hata Y, Murata T, et al. Pol J Pharmacol,1996,48(3):307
[23]Hirata C. Nakano K, Nakamura N, et al. Biochem Biophys Res Commun,1997,236(3):712
[24]Lewis G, Mervin K, Valter K, Maslim J, KaPPel PJ, Stone J, Fisher S. Limiting the proliferation and reactivity of retinal Muller cells during experimental retinal detachment:the value of oxygen supplementation. Am J Ophthalmol,1999;128(2):165-172
[25]Fisher S.K., Lewis G.P. Muller cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery:a review and reconsideration of recent data. Vision Research,2003,43:887-897.
[26]Lewis GP, Fisher SK. Muller cell outgrowth after retinal detachment:association with cone photoreceptors [J]. Invest Ophthalmol Vis Sci,2000,41:1542-1545
[27]孙晓东,张皙,胡宏慧,等.视网膜脱离时神经生长因子对Muller细胞中间丝蛋白表达的影响[J].眼科研究,2005,23：269
[28]Cao LH,Yu YC,Zhao JW, et al.Expression of natriuretic peptides in rat Muller cells[J].Neuroscience Letters,2004,365(3):176-179
[29]Harsda T, Harada C, Kohsaka S. Microglia-Muller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration[J].J Neuroscl 2002;22(21):9228-9236
[30]Walsh N, Valter K,Stone J. Cellular and subcelluler patterns of expression of BFGF and CNTF in the normal and light stressed adult rat retina[J].Exp Eye Res 2001;72(5):495-501
[31]Okk. H, Ikeda T, Honma Y. Gene expression of neurotrophins and their high-afinity Trk receptors in cultured human Muller cells[J].Ophthalmol Res2002;34(1):38-47.
[32]Taylor S,Srinivasan B,Wordinger RJ.Glutamate stimufates neurotrophin expression in cultured Muller cells[J]. Brain Res 2003;111(1-2):189-197.
[33]Harada T, Harada C. Function of glial cell network as a modulator of neural cell death during retinal degeneration[J]. Nippon Ganka Gakkai Zasshi,2004,108(11):674-681
[34]Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ. Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci USA.1998;95:3978-3983.
[35]Rosemarie G, Sandrine J, Vincent P. Brain-Derived Neurotrophic Factor Gene Delivery to Muller Glia Preserves Structure and Function of Light-Damaged Photoreceptors. IOVS, September 2005,46(9),3383-3391
[36]韦纯义,李爱冬,羊惠君.人胎视网膜发育过程中Fas、Fas-L、Bax和Bcl-2蛋白的表达[J].中华眼底病杂志,2001,17(1),55-57.
[37]Chen ST,Gentlemen SM,Gerey LJ. Distribution of beta-amyloid precursor and B-cell lymphoma protooncogene proteins in the rat retina after optic nerve transection or vascular lesion[J].J Neuropath Exp Neurology,1996,55(10):1073
[38]Chen ST,Gentleman SM,Garey IJ.Distribution of B-amyloid precursor and B-cel lymphoma protooncogene proteins in the rat retina after optic nerve transaction or vascular lesion[J].J Neuropathol Exp Neurol 1996;55(10):1073
[39]程欣,郑达人等.大鼠视网膜不完全性缺血引起细胞凋亡及bcl-2表达的研究.解剖科学进展,2000,6(2)：146.
[40]Ming-Hui S, Jong-Hwei SP, Sbow-Li C, et al. Photoreceptor protection against light damage by AAV-Mediated overexpression of Heme Oxygenase-1.IOVS,2007,48(12):5699-5707
[41]Fischer AJ, Reh TA.Muller glia are a potential source of neural regeneration in the postnatal chicken retina[J]. Nat Neurosci,2001,4(3):247-252
[42]Fischer AJ, McGuire CR, Dierks BD, et al. Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina[J].J Neurosci,2002,22(21):9387-9398
[43]Patrick Y, David AC. Responses of Muler glia to retinal injury in adult zebrafish [J]. Vision Research,2005,45(8):991-1002
[44]Das AV, Mallya KB, Zhao X, Ahmad F, Bhattacharya S, Thoreson WB, Hegde GV, Ahmad I. Neural stem cell properties of Muller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev Biol,2006,299:283-302.
[45]Rebecca L, Bernardos, Linda K, Barthel. Late-Stage Neuronal Progenitors in the Retina Are Radial Muller Glia That Function as Retinal Stem Cells[J]. J. Neurosci, June 27,2007,27(26):7028-7040.
[46]Andy JF,Omar G.Transitin, a nestin-related intermediate filament, is expressed by neural progenitors and can be induced in Muller glia in the chicken retina[J].J Comp Neurol,2005,484(1):1-14
[47]Fisher AJ, Reh TA, Potential of Muller glia to become neurogenic retinal progenitor cells[J].Glia,2003,43(1):70-76
2. Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK, LaNoue KF, Norbury CC, Quinn PG, Sandirasegarane L, Simpson IA. JDRF Diabetic Retinopathy Center Group. Diabetic retinopathy:Seeing beyond glucose-induced microvascular disease. Diabetes.2006;55:2401-2411.
3. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1:unleashing the protective properties of heme. Trends Immunol.2003;24:449-455.
4. Soares MP, Bach FH. Heme oxygenase-1:from biology to therapeutic potential. Trends Mol Med.2009;15:50-58.
5. Zhang M, Zhang BH, Chen L, An W. Overexpression of heme oxygenase-1 protects smooth muscle cells against oxidative injury and inhibits cell proliferation. Cell Res.2002;12:123-132.
6. Tamion F, Richard V, Renet S, Thuillez C. Intestinal preconditioning prevents inflammatory response by modulatinghemeoxygenase-1 expression in endotoxic shock model. Am J Physiol Gastrointest Liver Physiol.2007;293:G1308-1314.
7. Choi BM, Kim BR. Upregulation of heme oxygenase-1 by brazilin via the phosphatidylinositol 3-kinase/Akt and ERK pathways and its protective effect against oxidative injury. Eur J Pharmacol.2008;580:12-18.
8. Ndisang JF. Role of heme oxygenase in inflammation, insulin-signalling, diabetes and obesity. Mediators Inflamm.2010;2010:359732.
9. Kruger AL, Peterson SJ, Schwartzman ML, Fusco H, McClung JA, Weiss M, Shenouda S, Goodman AI, Goligorsky MS, Kappas A, Abraham NG. Up-regulation of heme oxygenase provides vascular protection in an animal model of diabetes through its antioxidant and antiapoptotic effects. J Pharmacol Exp Ther.2006;319:1144-1152.
10. Arai-Gaun S, Katai N, Kikuchi T, Kurokawa T, Ohta K, Yoshimura N. Heme oxygenase-1 induced in muller cells plays a protective role in retinal ischemia-reperfusion injury in rats. Invest Ophthalmol Vis Sci. 2004;45:4226-4232.
11. Sun MH, Pang JH, Chen SL, Han WH, Ho TC, Chen KJ, Kao LY, Lin KK, Tsao YP. Retinal protection from acute glaucoma-induced ischemia-reperfusion injury through pharmacologic induction of heme oxygenase-1. Invest Ophthalmol Vis Sci.2010;51:4798-4808.
12. Sun MH, Pang JH, Chen SL, Kuo PC, Chen KJ, Kao LY, Wu JY, Lin KK, Tsao YP. Photoreceptor protection against light damage by AAV-mediated overexpression of heme oxygenase-1. Invest Ophthalmol Vis Sci. 2007;48:5699-5707.
13. Lin JH, Villalon P, Martasek P, Abraham NG. Regulation of heme oxygenase gene expression by cobalt in rat liver and kidney. Eur J Biochem. 1990;192:577-582.
14. Shibahara S, Miiller RM, Taguchi H. Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem.1987;262:12889-12892.
15. Desbuards N, Rochefort GY, Schlecht D, Machet MC, Halimi JM, Eder V, Hyvelin JM, Antier D. Heme oxygenase-1 inducer hemin prevents vascular thrombosis. Thromb Haemost.2007;98:614-620.
16. Morita K, Lee MS, Her S. Possible relation of hemin-induced HO-1 expression to the upregulation of VEGF and BDNF mRNA levels in rat C6 glioma cells. J Mol Neurosci.2009;38:31-40.
17. Zijlstra GS, Brandsma CA, Harpe MF, Van Dam GM, Slebos DJ, Kerstjens HA, De Boer AH, Frijlink HW. Dry powder inhalation of hemin to induce heme oxygenase expression in the lung. Eur J Pharm Biopharm.2007;67:667-675.
18. Nussler AK, Hao L, Knobeloch D, Yao P, Nussler NC, Wang Z, Liu L, Ehnert S. Protective role of HO-1 for alcohol-dependent liver damage. Dig Dis. 2010;28:792-798.
19. Naughton P, Hoque M, Green CJ, Foresti R, Motterlini R. Interaction of heme with nitroxyl or nitric oxide amplifies heme oxygenase-1 induction:involvement of the transcription factor Nrf2. Cell Mol Biol (Noisy-le-grand).2002;48:885-894.
20. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res.2010;690:12-23.
21. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11:497-508.
22. Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys.2004;432:252-260.
23. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, Motterlini R. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J.2003;371:887-895.
24. Steinle JJ, Chin VC, Williams KP, Panjala SR. Beta-adrenergic receptor stimulation modulates iNOS protein levels through p38 and ERK1/2 signaling in human retinal endothelial cells. Exp Eye Res.2008;87:30-34.
25. Ye X, Xu G, Chang Q, Fan J, Sun Z, Qin Y, Jiang AC. ERK1/2 signaling pathways involved in VEGF release in diabetic rat retina. Invest Ophthalmol Vis Sci.2010;51:5226-5233.
26. Cukiernik M, Mukherjee S, Downey D, Chakabarti S. Heme oxygenase in the retina in diabetes. Curr Eye Res.2003;27:301-308.
27. Semenza G.L.,AgAni F.,Booth G., et al. Structural and functional analysis of hypoxia-inducible factor 1.Kidney Int.,1997,5(4) 1:553-555
28. Ozaki H., Yu AY., Della N., et al. Hypoxia inducible factor-lalpha is increased in ischemic retina:temporal and spatial correlation with VEGF expression. Investigative Ophthalmology and Visual Science,1999,40(1):182-189
29. Lukiw W.J.(2003), Ottlecz A., Lambrou G., Grueninger M., Finley J., Thompson H.W., et al. Coordinate activation of HIF-1 and NF-kappaB DNA bing and COX-2 and VEGF expression in retinal cells by hypoxia. Investigative Ophthalmology and Visual Science,4(10):4163-4170
30. Li, Q. F., Dai, A. G. (2004). Hypoxia Inducible factor-1 alpha correlates the expression of heme oxygenase 1 gene in pulmonary arteries of rat with hypoxia-induced pulmonary hypertension. Acta Biochimica et Biophysica Sinica,36(2):133-140
31. Kim B, Tang Q, Biswas PS. Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes. Am J Pathol; 2004; 16 5(5):2177-85
32. Tolentino MJ,Brucker AJ, Fosnot J.Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina; 2004;24(1);132-8.
33. Liu X, Cheng Y, Zhang S, et al. A necessary role of miR-222 and miR-221 in vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res. 2009;104:476-487.
34. Cheng Y, Liu X, Yang J, et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res.2009;105:158-166.
35. Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and anti sense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res.2007 100(11):1579-88.
36. Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol.2002; 12:735-739.
37. Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, Wang Z, Qiu S, Wang X, Yang G, Sun H, Tang Z, Wu Y, Zhu H, Fan J. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol.2011 Dec 20;29(36):4781-8.
38. Kenneth JL, Thomas DS. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-A ACT Method. Meth.2001;25:402-408.
39. Ndisang JF, Jadhav A.Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months.J Card Fail.2009;15:616-628.
40. Wang RQ, Nan YM, Wu WJ, Kong LB, Han F, Zhao SX, Kong L, Yu J. Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. Lipids Health Dis.2011;10:31.
41. Natarajan R, Fisher BJ, Fowler AA 3rd. Hypoxia inducible factor-1 modulates hemin-induced IL-8 secretion in microvascular endothelium. Microvasc Res. 2007;73:163-172.
42. Choi KM, Gibbons SJ, Nguyen TV, Stoltz GJ, Lurken MS, Ordog T, Szurszewski JH, Farrugia G. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology. 2008;135:2055-2064.
43. Fouad AA, Qureshi HA, Al-Sultan AI, Yacoubi MT, Ali AA. Protective effect of hemin against cadmium-induced testicular damage in rats. Toxicology. 2009;257:153-160.
44. Mazure NM, Brahimi-Horn MC, Berta MA, Benizri E, Bilton RL, Dayan F, Ginouves A, Berra E, Pouyssegur J. HIF-1:master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol.2004;68:971-980.
45. Ambati J, Chalam KV, Chawla DK, D'Angio CT, Guillet EG, Rose SJ, Vanderlinde RE, Ambati BK. Elevated gamma aminobutyricacid, glutamate, and vascular endothelial growth factor levelsin the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol.1997; 115:1161-1166.
46. Hofseth LJ, Hussain SP, Harris CC. p53:25 years after its discovery. Trends Pharmacol. Sci.2004;25:177-181.
47. Wang X, Ye XL, Liu R, Chen HL, Bai H, Liang X, Zhang XD, Wang Z, Li WL, Hai CX. Antioxidant activities of oleanolic acid in vitro:possible role of Nrf2 and MAP kinases. Chem Biol Interact.2010;184:328-337.
48. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A. Miiller cells in the healthy and diseased retina. Prog Retin Eye Res.2006;25:397-424.
49. de Melo Reis RA, Ventura AL, Schitine CS, de Mello MC, de Mello FG. Miiller glia as an active compartment modulating nervous activity in the vertebrate retina: neurotransmitters and trophic factors. Neurochem Res.2008;33:1466-1474.
50. Liu W, Xu GZ, Jiang CH, Da CD. Expression of macrophage colony-stimulating factor (M-CSF) and its receptor in streptozotocin-induced diabetic rats. Curr Eye Res.2009;34:123-133.
51. Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Exp Diabetes Res.2007;2007:43603.
52. Valdivia A, Perez-Alvarez S, Aroca-Aguilar JD, Ikuta I, Jordan J. Superoxide dismutases:a physiopharmacological update. J Physiol Biochem. 2009;65:195-208.
53. Turan B. Role of antioxidants in redox regulation of diabetic cardiovascular complications. Curr Pharm Biotechnol.2010;11:819-836.
54. Du Y, Miller CM, Kern TS. Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic Biol Med.2003;35:1491-1499.
55. Craven PA, Melhem MF, Phillips SL, DeRubertis FR. Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. Diabetes.2001;50:2114-2125.
56. DeRubertis FR, Craven PA, Melhem MF, Salah EM. Attenuation of renal injury in db/db mice overexpressing superoxide dismutase:evidence for reduced superoxide-nitric oxide interaction. Diabetes.2004;53:762-768.
57. Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia:implications for diabetic retinopathy. Diabetes. 2004;53:2931-2938.
58. Arden GB, Sivaprasad S. Hypoxia and Oxidative Stress in the Causation of Diabetic Retinopathy. Curr Diabetes Rev.2011 Sep 15. [Epub ahead of print]
59. Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS. Hypoxia-inducible factor 1 alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol.2003;23:359-369.
60. Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA. Hypoxia inducible factor-1 alpha is increased in ischemic retina:temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci.1999;40:182-189.
61. Schmid T, Zhou J, Brune B. HIF-1 and p53:communication of transcription factors under hypoxia. J Cell Mol Med.2004;8:423-431.
62. Lin M, Chen Y, Jin J, Hu Y, Zhou KK, Zhu M, Le YZ, Ge J, Johnson RS, Ma JX. Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Muller cells. Diabetologia.2011;54:1554-1566.
63. Nakamura M, Kanamori A, Negi A. Diabetes mellitus as a risk factor for glaucomatous optic neuropathy. Ophthalmologica.2005;219:1-10.
64. van Dijk HW, Verbraak FD, Kok PH, Garvin MK, Sonka M, Lee K, Devries JH, Michels RP, van Velthoven ME, Schlingemann RO, Abramoff MD. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest Ophthalmol Vis Sci.2010;51:3660-3665.
65. Panahian N, Yoshiura M, Maines MD. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J Neurochem.1999;72:1187-1203.
66. Adamis AP, Miller JW, Bernal MT, D'Amico DJ, Folkman J, Yeo TK, Yeo KT. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol.1994;118:445-450.
67. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA.1995;92:10457-10461.
68. Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29:789-791.
69. Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP. Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol. 2002;160:501-509.
70. Yu DY, Cringle SJ, Su EN, Yu PK, Jerums G, Cooper ME. Pathogenesis and intervention strategies in diabetic retinopathy. Clin Experiment Ophthalmol. 2001;29:164-166.
71. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327-1334.
72. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(Suppl.1):S62-S69.
73. Wright, G.W. and R.M. Simon. A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003;19:2448-2455.
74. Yang, H., N. Crawford, L. Lukes, R. Finney, M. Lancaster, and K.W. Hunter. Metastasis predictive signature profiles pre-exist in normal tissues. Clin Exp Metastasis 2005;22:593-603.
75. Clarke, R., H.W. Ressom, A. Wang, J. Xuan, M.C. Liu, E.A. Gehan, and Y. Wang. The properties of high-dimensional data spaces:implications for exploring gene and protein expression data. Nat Rev Cancer.2008; 8:37-49.
76. Ramoni, M.F., P. Sebastiani, and I.S. Kohane. Cluster analysis of gene expression dynamics. Proc Natl Acad Sci USA.2002; 99:9121-9126.
77. Miller, L.D., P.M. Long, L. Wong, S. Mukherjee, L.M. McShane, and E.T. Liu. Optimal gene expression analysis by microarrays. Cancer Cell.2002; 2:353-361.
78. Yi, M., J.D. Horton, J.C. Cohen, H.H. Hobbs, and R.M. Stephens. WholePathwayScope:a comprehensive pathway-based analysis tool for high-throughput data. BMC Bioinformatics.2006;7:30.
79. Je-Gun, J, Kyu-Baek, H, Jin-Wu, N, Soo-Jin, K, and Byoung-Tak, Z. Discovery of microRNA-mRNA modules via population-based probabilistic learning. Bioinfo.2007;23:1141.
80. Reut, S, Daniel, L, Moshe, Oren, Yitzhak, P. Global and local architecture of the mammalian microRNA-transcription factor regulatory network. PLOS One.2007; 3:1291
81.Bartel DP. Micro RNAs:genomics, biogenesis, mechanism and function. Cell.2004;116(2):281-297.
82.Poy MN, Eliasson L, Krutzfeidt J, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature.2004;432(7014):226-230.
83.Plaisance V, Abderrahmani A, Perret-Menoud V et al. MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells. JBiol Chem.2006;281(37):26932-42.
84.He A, Zhu L, Gupta N, et al. Over-expression of miR-29, highly upregulated in diabetic rats, leads to insulin resistance in 3T3-LI adipocytes. Mol Endocrinol. 2007;21(11):2785-94.
85.Xiao J, Luo X, Lin H, et al. MicroRNA miR-133 represses HERG K+channel expression contributing to QT prolongation in diabetic heans. J Biol Chem. 2007;282(17):12363-7.
86. Duan Q, Wang X, Gong W, Ni L, Chen C, He X, Chen F, Yang L, Wang P, Wang DW. ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS One.2012;7(2):e31518.
87. Schwarzenbach H, Milde-Langosch K, Steinbach B, Muller V, Pantel K. Diagnostic potential of PTEN-targeting miR-214 in the blood of breast cancer patients. Breast Cancer Res Treat.2012 Feb 19. [Epub ahead of print]
88. Peng RQ, Wan HY, Li HF, Liu M, Li X, Tang H. MicroRNA-214 Suppresses The Growth and Invasiveness of Cervical Cancer Cells by Targeting UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 7. J Biol Chem.2012 Mar 7. [Epub ahead of print]
89. Chen YQ, Wang XX, Yao XM, Zhang DL, Yang XF, Tian SF, Wang NS. Abated microRNA-195 expression protected mesangial cells from apoptosis in early diabetic renal injury in mice. J Nephrol.2011 Oct 4:0. doi:10.5301/jn.5000034. [Epub ahead of print]
90. Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ, Seals DR. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol.2012;47(1):45-51.
91. Aurora AB, Mahmoud AI, Luo X, Johnson BA, van Rooij E, Matsuzaki S, Humphries KM, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. J Clin Invest.2012;122(4):1222-32.
92. van Mil A, Grundmann S, Goumans MJ, Lei Z, Oerlemans MI, Jaksani S, Doevendans PA, Sluijter JP. MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release. Cardiovasc Res. 2012;93(4):655-65.
93. Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X. MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol. 2012;227(2):772-83.
94. Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-kappaB signaling. JMol Cell Biol.2011;3(3):159-66.
95. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell.2010;39(4):493-506.
96. Zhao J, Gong AY, Zhou R, Liu J, Eischeid AN, Chen XM. Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-a-induced transcription of proinflammatory genes in liver epithelial cells.J Immunol. 2012;188(3):1266-74.
97. Visone R, Veronese A, Balatti V, Croce CM. MiR-181b:new perspective to evaluate disease progression in chronic lymphocytic leukemia. Oncotarget. 2012;3(2):195-202.
98. Visone R, Veronese A, Rassenti LZ, Balatti V, Pearl DK, Acunzo M, Volinia S, Taccioli C, Kipps TJ, Croce CM. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood.2011;118(11):3072-9.
[1]John E Dowling.Retina.1987,7-9.
[2]Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells[J]. Vision Res,1997,37(24):3483.
[3]Dreher Z, Robinson SR, Distler C. Muller cells in vascular and avascular retina:a survey of seven mammals[J].J Comp Neur,1992,23:59-80
[4]Schwartz EA, Tachibana M. Electrophysiology of glutamate and sodium co-transport in a glial cell of the salamander retina[J].J Physiol,1990,426:43-80
[5]Newman EA. Acid efflux from retinal glial cells generated by sodium bicarbonate cotransport[J]. J Neurosci,1996,16:159-168
[6]Reichelt W, Hernandez M, Damian RT, et al. Damian RT GABAA receptor currents recorded from Muller glial cells of the baboon (Papiocynocephalus) retina[J].Neurosci Lett,1996,203:159-162
[7]Kim LB,Kim KY,Joo CK,et al.Reaction of Muller cells after increased intraocular pressure in the rat retina[J].Exp Brain Res,1998,121:419-424
[8]Napper GA, Pianta MJ, Kalloniatis M.Reduced glutamate uptake by retinal glial cells under ischemic/hypoxic condition[J].Vis Neurosci,1999,16(1):149
[9]Napper GA, Kalloniatis M. Neurochemical changes following postmortem ischemia in the rat retina[J].Vis Neurosci,1999,16(6):1169
[10]Winkler BS, Arnold MJ, Brassell MA, el al. Energy metabolism in human retinal Muller cells[J]. Invest Ophtholmol Vis, Sci,2000,41(10):3183
[11]Harada T, Harada C, Watanabe M, et al. Functions of the two glutamate transporter, GLAST and GLT-1 in the retina[J].ProcNatl Acad Sci USA,1998, 95(8):4663
[12]Huster D, Reichenbach A, Reichelt W. The glutathione content of retinal Muller cells:effect of pathological conditions[J].N eurothem Int,2000,36(4-5):461
[13]Gohdo T, Ueda H, Ohno S, et al.Ophthalmic Res,2001,33(5):298
[14]Akiyama H,Nakazawa T,Shimura M,et al.Neuroreport,2002,13:2103
[15]Bignami A, Dahl D,Exp Eye Res,1979,28(1):63
[16]Chu Y, Humphrey MF, Alder W,et al.Immunocytochemical localization of basic fibroblast growth factor and glial fibrillary acidic protein after laser photocoagulation in the Royl college surgeons rat. Aust NZ J Ophthalmol,1998;26(1):87
[17]Chen H,Weber AJ.Glia,2002,38(2):115
[18]Barber AJ, Antonetti DA, Gardner TW.Altered expression of retinal occluding and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group.Invest Ophthalmol Vis Sci,2000;41:3561-3568
[19]I.i Q, Zemel E, Miller B, et al. Exp Eye Res,2002.74(5):615
[20]Lieth E,Barber AJ,Xu B,et al. Diabetes,1998,47(5):815
[21]Ishikawa A, Ishiguro S, Tamai M. Changes in GAB A metabolism in streptozotoc induced diabetic rat retinas. Curr Eye Res,1996; 15:63-71
[22]Sueishi K, Hata Y, Murata T, et al. Pol J Pharmacol,1996,48(3):307
[23]Hirata C. Nakano K, Nakamura N, et al. Biochem Biophys Res Commun,1997,236(3):712
[24]Lewis G, Mervin K, Valter K, Maslim J, KaPPel PJ, Stone J, Fisher S. Limiting the proliferation and reactivity of retinal Muller cells during experimental retinal detachment:the value of oxygen supplementation. Am J Ophthalmol,1999;128(2):165-172
[25]Fisher S.K., Lewis G.P. Muller cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery:a review and reconsideration of recent data. Vision Research,2003,43:887-897.
[26]Lewis GP, Fisher SK. Muller cell outgrowth after retinal detachment:association with cone photoreceptors [J]. Invest Ophthalmol Vis Sci,2000,41:1542-1545
[27]孙晓东,张皙,胡宏慧,等.视网膜脱离时神经生长因子对Muller细胞中间丝蛋白表达的影响[J].眼科研究,2005,23：269
[28]Cao LH,Yu YC,Zhao JW, et al.Expression of natriuretic peptides in rat Muller cells[J].Neuroscience Letters,2004,365(3):176-179
[29]Harsda T, Harada C, Kohsaka S. Microglia-Muller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration[J].J Neuroscl 2002;22(21):9228-9236
[30]Walsh N, Valter K,Stone J. Cellular and subcelluler patterns of expression of BFGF and CNTF in the normal and light stressed adult rat retina[J].Exp Eye Res 2001;72(5):495-501
[31]Okk. H, Ikeda T, Honma Y. Gene expression of neurotrophins and their high-afinity Trk receptors in cultured human Muller cells[J].Ophthalmol Res2002;34(1):38-47.
[32]Taylor S,Srinivasan B,Wordinger RJ.Glutamate stimufates neurotrophin expression in cultured Muller cells[J]. Brain Res 2003;111(1-2):189-197.
[33]Harada T, Harada C. Function of glial cell network as a modulator of neural cell death during retinal degeneration[J]. Nippon Ganka Gakkai Zasshi,2004,108(11):674-681
[34]Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ. Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci USA.1998;95:3978-3983.
[35]Rosemarie G, Sandrine J, Vincent P. Brain-Derived Neurotrophic Factor Gene Delivery to Muller Glia Preserves Structure and Function of Light-Damaged Photoreceptors. IOVS, September 2005,46(9),3383-3391
[36]韦纯义,李爱冬,羊惠君.人胎视网膜发育过程中Fas、Fas-L、Bax和Bcl-2蛋白的表达[J].中华眼底病杂志,2001,17(1),55-57.
[37]Chen ST,Gentlemen SM,Gerey LJ. Distribution of beta-amyloid precursor and B-cell lymphoma protooncogene proteins in the rat retina after optic nerve transection or vascular lesion[J].J Neuropath Exp Neurology,1996,55(10):1073
[38]Chen ST,Gentleman SM,Garey IJ.Distribution of B-amyloid precursor and B-cel lymphoma protooncogene proteins in the rat retina after optic nerve transaction or vascular lesion[J].J Neuropathol Exp Neurol 1996;55(10):1073
[39]程欣,郑达人等.大鼠视网膜不完全性缺血引起细胞凋亡及bcl-2表达的研究.解剖科学进展,2000,6(2)：146.
[40]Ming-Hui S, Jong-Hwei SP, Sbow-Li C, et al. Photoreceptor protection against light damage by AAV-Mediated overexpression of Heme Oxygenase-1.IOVS,2007,48(12):5699-5707
[41]Fischer AJ, Reh TA.Muller glia are a potential source of neural regeneration in the postnatal chicken retina[J]. Nat Neurosci,2001,4(3):247-252
[42]Fischer AJ, McGuire CR, Dierks BD, et al. Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina[J].J Neurosci,2002,22(21):9387-9398
[43]Patrick Y, David AC. Responses of Muler glia to retinal injury in adult zebrafish [J]. Vision Research,2005,45(8):991-1002
[44]Das AV, Mallya KB, Zhao X, Ahmad F, Bhattacharya S, Thoreson WB, Hegde GV, Ahmad I. Neural stem cell properties of Muller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev Biol,2006,299:283-302.
[45]Rebecca L, Bernardos, Linda K, Barthel. Late-Stage Neuronal Progenitors in the Retina Are Radial Muller Glia That Function as Retinal Stem Cells[J]. J. Neurosci, June 27,2007,27(26):7028-7040.
[46]Andy JF,Omar G.Transitin, a nestin-related intermediate filament, is expressed by neural progenitors and can be induced in Muller glia in the chicken retina[J].J Comp Neurol,2005,484(1):1-14
[47]Fisher AJ, Reh TA, Potential of Muller glia to become neurogenic retinal progenitor cells[J].Glia,2003,43(1):70-76