Effects of Krüppel-like factor 7 on the survival of retinal ganglion cells and electroretinogram after retinal ischemia-reperfusion injury_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Zongyuan , Yang Ning , Luo Jinyuan , Yang Jiayi , He Tao ,  Xing Yiqiao

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding?author：

Xing Yiqiao, Email: yiqiao_xing57@whu.edu.cn

Keywords：

Kruppel-like transcription factors; Reperfusion injury; Retinal ganglion cells; Electroretinography; Animal Experimentation

DOI：

10.3760/cma.j.cn511434-20200602-00256

Video：

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Objective To investigate the effects of Krüppel-like factor 7 (KLF7) on the survival of retinal ganglion cells (RGCs) and electroretinogram (ERG) after retinal ischemia-reperfusion (RIR) injury in mice.Methods A total of 126 male C57BL/6J mice were randomly divided into normal group, RIR group, normal-KLF7 group, normal-green fluorescent protein (GFP) group, RIR-KLF7 group and RIR-GFP group. At the age of 8 weeks, mice of normal-KLF7 group and RIR-KLF7 group were intravitreally injected 1ul of 1.0×10¹² vg/ml adeno-associated virus overexpressing KLF7 (AAV2-KLF7-GFP). Mice of normal-GFP group and RIR-GFP group were injected adeno-associated virus of AAV2-GFP with the same titer. At the age of 11 weeks, RIR injury was induced in mice of RIR group, RIR-KLF7 group and RIR-GFP group, and intraocular pressure was measured. Retinal cryosections were used to access the efficacy of virus transfection 4 weeks after AAV2-KLF7-GFP transfer. 7 days after RIR injury, RGCs’ survival rate was observed and quantified by immunofluorescent staining. ERG was performed to observe the differences in amplitudes and incubation period of scotopic ERG a-, b-wave, oscillatory potentials (Ops), photopic negative responses (PhNR). Optomotor response was performed to observe the differences of visual acuity. Expression of KLF7 was detected by western blot 4 weeks after AAV2-KLF7-GFP transfer.Results Compared with normal group, RGCs’ survival rates, amplitudes of ERG a-, b-wave, Ops, PhNR and visual acuity of mice in RIR group were decreased, and the differences were statistically significant (t=12.860, 7.157, 5.735, 8.953, 4.744, 9.887; P＜0.05). With the increase of light intensity, the amplitudes of scotopic ERG a- and b-wave were gradually increased while the incubation period was gradually shortened. Compared with RIR group, RGCs’ survival rates, amplitudes of ERG a-, b-wave, Ops, PhNR and visual acuity of mice in RIR-KLF7 group were increased, and the differences were statistically significant (t=6.350, 3.253, 3.695, 5.825, 5.325, 4.591; P＜0.05). Protein level of KLF7 was up-regulated in normal-KLF7 group than those in normal group, and the difference was statistically significant (t=4.105, P＜0.01).Conclusion Overexpression of KLF7 can improve RGCs’ survival rates and preserve the electrophysiological function.

Citation： Li Zongyuan, Yang Ning, Luo Jinyuan, Yang Jiayi, He Tao, Xing Yiqiao. Effects of Krüppel-like factor 7 on the survival of retinal ganglion cells and electroretinogram after retinal ischemia-reperfusion injury. Chinese Journal of Ocular Fundus Diseases, 2020, 36(11): 846-852. doi: 10.3760/cma.j.cn511434-20200602-00256 Copy

1.	Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis[J]. Ophthalmology, 2014, 121(11): 2081-2090. DOI: 10.1016/j.ophtha.2014.05.013.
2.	Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020[J]. Br J Ophthalmol, 2006, 90(3): 262-267. DOI: 10.1136/bjo.2005.081224.
3.	Laub F, Aldabe R, Friedrich V Jr, et al. Developmental expression of mouse Krüppel-like transcription factor KLF7 suggests a potential role in neurogenesis[J]. Dev Biol, 2001, 233(2): 305-318. DOI: 10.1006/dbio.2001.0243.
4.	Moore DL, Blackmore MG, Hu Y, et al. KLF family members regulate intrinsic axon regeneration ability[J]. Science, 2009, 326(5950): 298-301. DOI: 10.1126/science.1175737.
5.	Black AR, Black JD, Azizkhan-Clifford J. Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer[J]. J Cell Physiol, 2001, 188(2): 143-160. DOI: 10.1002/jcp.1111.
6.	Laub F, Lei L, Sumiyoshi H, et al. Transcription factor KLF7 is important for neuronal morphogenesis in selected regions of the nervous system[J]. Mol Cell Biol, 2005, 25(13): 5699-5711. DOI: 10.1128/MCB.25.13.5699-5711.2005.
7.	Luo J, He T, Yang J, et al. SIRT1 is required for the neuroprotection of resveratrol on retinal ganglion cells after retinal ischemia-reperfusion injury in mice[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(2): 335-344. DOI: 10.1007/s00417-019-04580-z.
8.	Connor KM, Krah NM, Dennison RJ, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis[J]. Nat Protoc, 2009, 4(11): 1565-1573. DOI: 10.1038/nprot.2009.187.
9.	Shen Y, Luo X, Liu S, et al. Rod bipolar cells dysfunction occurs before ganglion cells loss in excitotoxin-damaged mouse retina[J/OL]. Cell Death Dis, 2019, 10(12): 905[2019-12-02]. https://pubmed.ncbi.nlm.nih.gov/31787761/. DOI: 10.1038/s41419-019-2140-x.
10.	Prusky GT, Alam NM, Douglas RM. Enhancement of vision by monocular deprivation in adult mice[J]. J Neurosci, 2006, 26(45): 11554-11561. DOI: 10.1523/JNEUROSCI.3396-06.2006.
11.	劉一帆, 沈吟. 低濃度氯喹保護成年小鼠視網膜神經節細胞抵抗N-甲基-D-天冬氨酸的興奮性毒性作用[J]. 中華眼底病雜志, 2020, 36(4): 295-301. DOI: 10.3760/cma.j.cn511434-20190903-00275.Liu YF, Shen Y. Low-dose chloroquine mediated neuroprotection against n-methyl-d-aspartate induced excitotoxicity in adult mice[J]. Chin J Ocul Fundus Dis, 2020, 36(4): 295-301. DOI: 10.3760/cma.j.cn511434-20190903-00275.
12.	Matsumoto N, Laub F, Aldabe R, et al. Cloning the cDNA for a new human zinc finger protein defines a group of closely related Krüppel-like transcription factors[J]. J Biol Chem, 1998, 273(43): 28229-28237. DOI: 10.1074/jbc.273.43.28229.
13.	Wang Z, Winsor K, Nienhaus C, et al. Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury[J]. Neurobiol Dis, 2017, 99: 24-35. DOI: 10.1016/j.nbd.2016.12.010.
14.	Wang Y, Li WY, Jia H, et al. KLF7-transfected Schwann cell graft transplantation promotes sciatic nerve regeneration[J]. Neuroscience, 2017, 340: 319-332. DOI: 10.1016/j.neuroscience.2016.10.069.
15.	Tang X, Liu K, Hamblin MH, et al. Genetic deletion of Krüppel-like factor 11 aggravates ischemic brain injury[J]. Mol Neurobiol, 2018, 55(4): 2911-2921. DOI: 10.1007/s12035-017-0556-9.
16.	Minhas G, Sharma J, Khan N. Cellular stress response and immune signaling in retinal ischemia-reperfusion injury[J/OL]. Front Immunol, 2016, 7: 444[2016-08-24]. https://pubmed.ncbi.nlm.nih.gov/27822213/. DOI: 10.3389/fimmu.2016.00444.
17.	Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement[J]. Ophthalmology, 2012, 119(5): 979-986. DOI: 10.1016/j.ophtha.2011.11.003.
18.	隋源, 李雪麗, 勾曉梅, 等. 視網膜缺血再灌注后視網膜的病理變化及造模前后CREB的表達[J]. 臨床眼科雜志, 2017, 25(6): 555-559. DOI: 10.3969/j.issn.1006-8422.2017.06.023.Sui Y, Li XL, Gou XM, et al. Expression of CREB in a rat model of retinal ischemia reperfusion[J]. J Clin Ophthalmol, 2017, 25(6): 555-559. DOI: 10.3969/j.issn.1006-8422.2017.06.023.
19.	郭苗, 顏華. 視網膜缺血再灌注損傷的發病機制與治療進展[J]. 中華眼底病雜志, 2020, 36(6): 483-488. DOI: 10.3760/cma.j.cn511434-20180807-00276.Guo M, Yan H. Research progress in the mechanism and treatment of retinal ischemia reperfusion injury[J]. Chin J Ocul Fundus Dis, 2020, 36(6): 483-488. DOI: 10.3760/cma.j.cn511434-20180807-00276.
20.	Harvey AR, Kamphuis W, Eggers R, et al. Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors[J]. Mol Cell Neurosci, 2002, 21(1): 141-157. DOI: 10.1006/mcne.2002.1168.
21.	Jain V, Ravindran E, Dhingra NK. Differential expression of Brn3 transcription factors in intrinsically photosensitive retinal ganglion cells in mouse[J]. J Comp Neurol, 2012, 520(4): 742-755. DOI: 10.1002/cne.22765.
22.	Chrysostomou V, Crowston JG. The photopic negative response of the mouse electroretinogram: reduction by acute elevation of intraocular pressure[J]. Invest Ophthalmol Vis Sci, 2013, 54(7): 4691-4697. DOI: 10.1167/iovs.13-12415.
23.	雷博. 合理選擇視網膜電圖檢查指標客觀了解內層視網膜的功能[J]. 中華實驗眼科雜志, 2016, 34(4): 289-292. DOI: 10.3760/cma.j.issn.2095-0160.2016.04.001.Lei B. Towards objective assessment of the inner retinal functions[J]. Chin J Exp Ophthalmol, 2016, 34(4): 289-292. DOI: 10.3760/cma.j.issn.2095-0160.2016.04.001.
24.	Wilsey LJ, Fortune B. Electroretinography in glaucoma diagnosis[J]. Curr Opin Ophthalmol, 2016, 27(2): 118-124. DOI: 10.1097/ICU.0000000000000241.
25.	Yune TY, Lee JY, Jung GY, et al. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury[J]. J Neurosci, 2007, 27(29): 7751-7761. DOI: 10.1523/JNEUROSCI.1661-07.2007.
26.	Weymouth AE, Vingrys AJ. Rodent electroretinography: methods for extraction and interpretation of rod and cone responses[J]. Prog Retin Eye Res, 2008, 27(1): 1-44. DOI: 10.1016/j.preteyeres.2007.09.003.
27.	Wachtmeister L. Oscillatory potentials in the retina: what do they reveal[J]. Prog Retin Eye Res, 1998, 17(4): 485-521. DOI: 10.1016/s1350-9462(98)00006-8.
28.	Burroughs SL, Kaja S, Koulen P. Quantification of deficits in spatial visual function of mouse models for glaucoma[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3654-3659. DOI: 10.1167/iovs.10-7106.

1. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis[J]. Ophthalmology, 2014, 121(11): 2081-2090. DOI: 10.1016/j.ophtha.2014.05.013.
2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020[J]. Br J Ophthalmol, 2006, 90(3): 262-267. DOI: 10.1136/bjo.2005.081224.
3. Laub F, Aldabe R, Friedrich V Jr, et al. Developmental expression of mouse Krüppel-like transcription factor KLF7 suggests a potential role in neurogenesis[J]. Dev Biol, 2001, 233(2): 305-318. DOI: 10.1006/dbio.2001.0243.
4. Moore DL, Blackmore MG, Hu Y, et al. KLF family members regulate intrinsic axon regeneration ability[J]. Science, 2009, 326(5950): 298-301. DOI: 10.1126/science.1175737.
5. Black AR, Black JD, Azizkhan-Clifford J. Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer[J]. J Cell Physiol, 2001, 188(2): 143-160. DOI: 10.1002/jcp.1111.
6. Laub F, Lei L, Sumiyoshi H, et al. Transcription factor KLF7 is important for neuronal morphogenesis in selected regions of the nervous system[J]. Mol Cell Biol, 2005, 25(13): 5699-5711. DOI: 10.1128/MCB.25.13.5699-5711.2005.
7. Luo J, He T, Yang J, et al. SIRT1 is required for the neuroprotection of resveratrol on retinal ganglion cells after retinal ischemia-reperfusion injury in mice[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(2): 335-344. DOI: 10.1007/s00417-019-04580-z.
8. Connor KM, Krah NM, Dennison RJ, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis[J]. Nat Protoc, 2009, 4(11): 1565-1573. DOI: 10.1038/nprot.2009.187.
9. Shen Y, Luo X, Liu S, et al. Rod bipolar cells dysfunction occurs before ganglion cells loss in excitotoxin-damaged mouse retina[J/OL]. Cell Death Dis, 2019, 10(12): 905[2019-12-02]. https://pubmed.ncbi.nlm.nih.gov/31787761/. DOI: 10.1038/s41419-019-2140-x.
10. Prusky GT, Alam NM, Douglas RM. Enhancement of vision by monocular deprivation in adult mice[J]. J Neurosci, 2006, 26(45): 11554-11561. DOI: 10.1523/JNEUROSCI.3396-06.2006.
11. 劉一帆, 沈吟. 低濃度氯喹保護成年小鼠視網膜神經節細胞抵抗N-甲基-D-天冬氨酸的興奮性毒性作用[J]. 中華眼底病雜志, 2020, 36(4): 295-301. DOI: 10.3760/cma.j.cn511434-20190903-00275.Liu YF, Shen Y. Low-dose chloroquine mediated neuroprotection against n-methyl-d-aspartate induced excitotoxicity in adult mice[J]. Chin J Ocul Fundus Dis, 2020, 36(4): 295-301. DOI: 10.3760/cma.j.cn511434-20190903-00275.
12. Matsumoto N, Laub F, Aldabe R, et al. Cloning the cDNA for a new human zinc finger protein defines a group of closely related Krüppel-like transcription factors[J]. J Biol Chem, 1998, 273(43): 28229-28237. DOI: 10.1074/jbc.273.43.28229.
13. Wang Z, Winsor K, Nienhaus C, et al. Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury[J]. Neurobiol Dis, 2017, 99: 24-35. DOI: 10.1016/j.nbd.2016.12.010.
14. Wang Y, Li WY, Jia H, et al. KLF7-transfected Schwann cell graft transplantation promotes sciatic nerve regeneration[J]. Neuroscience, 2017, 340: 319-332. DOI: 10.1016/j.neuroscience.2016.10.069.
15. Tang X, Liu K, Hamblin MH, et al. Genetic deletion of Krüppel-like factor 11 aggravates ischemic brain injury[J]. Mol Neurobiol, 2018, 55(4): 2911-2921. DOI: 10.1007/s12035-017-0556-9.
16. Minhas G, Sharma J, Khan N. Cellular stress response and immune signaling in retinal ischemia-reperfusion injury[J/OL]. Front Immunol, 2016, 7: 444[2016-08-24]. https://pubmed.ncbi.nlm.nih.gov/27822213/. DOI: 10.3389/fimmu.2016.00444.
17. Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement[J]. Ophthalmology, 2012, 119(5): 979-986. DOI: 10.1016/j.ophtha.2011.11.003.
18. 隋源, 李雪麗, 勾曉梅, 等. 視網膜缺血再灌注后視網膜的病理變化及造模前后CREB的表達[J]. 臨床眼科雜志, 2017, 25(6): 555-559. DOI: 10.3969/j.issn.1006-8422.2017.06.023.Sui Y, Li XL, Gou XM, et al. Expression of CREB in a rat model of retinal ischemia reperfusion[J]. J Clin Ophthalmol, 2017, 25(6): 555-559. DOI: 10.3969/j.issn.1006-8422.2017.06.023.
19. 郭苗, 顏華. 視網膜缺血再灌注損傷的發病機制與治療進展[J]. 中華眼底病雜志, 2020, 36(6): 483-488. DOI: 10.3760/cma.j.cn511434-20180807-00276.Guo M, Yan H. Research progress in the mechanism and treatment of retinal ischemia reperfusion injury[J]. Chin J Ocul Fundus Dis, 2020, 36(6): 483-488. DOI: 10.3760/cma.j.cn511434-20180807-00276.
20. Harvey AR, Kamphuis W, Eggers R, et al. Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors[J]. Mol Cell Neurosci, 2002, 21(1): 141-157. DOI: 10.1006/mcne.2002.1168.
21. Jain V, Ravindran E, Dhingra NK. Differential expression of Brn3 transcription factors in intrinsically photosensitive retinal ganglion cells in mouse[J]. J Comp Neurol, 2012, 520(4): 742-755. DOI: 10.1002/cne.22765.
22. Chrysostomou V, Crowston JG. The photopic negative response of the mouse electroretinogram: reduction by acute elevation of intraocular pressure[J]. Invest Ophthalmol Vis Sci, 2013, 54(7): 4691-4697. DOI: 10.1167/iovs.13-12415.
23. 雷博. 合理選擇視網膜電圖檢查指標客觀了解內層視網膜的功能[J]. 中華實驗眼科雜志, 2016, 34(4): 289-292. DOI: 10.3760/cma.j.issn.2095-0160.2016.04.001.Lei B. Towards objective assessment of the inner retinal functions[J]. Chin J Exp Ophthalmol, 2016, 34(4): 289-292. DOI: 10.3760/cma.j.issn.2095-0160.2016.04.001.
24. Wilsey LJ, Fortune B. Electroretinography in glaucoma diagnosis[J]. Curr Opin Ophthalmol, 2016, 27(2): 118-124. DOI: 10.1097/ICU.0000000000000241.
25. Yune TY, Lee JY, Jung GY, et al. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury[J]. J Neurosci, 2007, 27(29): 7751-7761. DOI: 10.1523/JNEUROSCI.1661-07.2007.
26. Weymouth AE, Vingrys AJ. Rodent electroretinography: methods for extraction and interpretation of rod and cone responses[J]. Prog Retin Eye Res, 2008, 27(1): 1-44. DOI: 10.1016/j.preteyeres.2007.09.003.
27. Wachtmeister L. Oscillatory potentials in the retina: what do they reveal[J]. Prog Retin Eye Res, 1998, 17(4): 485-521. DOI: 10.1016/s1350-9462(98)00006-8.
28. Burroughs SL, Kaja S, Koulen P. Quantification of deficits in spatial visual function of mouse models for glaucoma[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3654-3659. DOI: 10.1167/iovs.10-7106.

Chinese Journal of Ocular Fundus Diseases

Effects of Krüppel-like factor 7 on the survival of retinal ganglion cells and electroretinogram after retinal ischemia-reperfusion injury

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