The current status and progress of the pathological changes and related molecular mechanisms of neuroretinal injury in diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Shufeng , Hu Jianyan , Li Tingting ,  Wu Qiang

Department of Ophthalmology, The Sixth People's Hospital Affiliated to Shanghai JiaoTong University, Shanghai 200233, China;

Corresponding author：

Wu Qiang, Email: qiang.wu@shsmu.edu.cn

Keywords：

Diabetic retinopathy/pathology; Optic nerve injuries; Apoptosis; Autophagy; Review

DOI：

10.3760/cma.j.issn.1005-1015.2017.03.025

Video：

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The neuroretinal injuries of diabetic retinopathy (DR) include retinal neuronal damage and reactive gliosis, both of which are induced by hyperglycemia and presented as early features of DR. They promote to develop mutually and accelerate the progression of DR. The molecular mechanisms study of neuronal damage mainly focuses on the alterations of extracellular environment and related signaling pathways, include inflammation, oxidative stress, endoplasmic reticulum stress, the formation of advanced glycation end products, glutamate toxicity and so on. These alterations mainly result in neuronal apoptosis and autophagy. The damaged neurons activate the glial cells with apparent changes in morphology, cell counts and the level of intracellular protein expression. In non-proliferative DR, glial cells are moderately hypertrophic and slightly increased in numbers. In proliferative DR, there is a significant rise in glial cell number with enhanced level of inflammatory factors and vascular active substances which lead a further neuronal damage. Signaling pathways of extracellular signal-regulated kinase 1/2, c-Fos and p38 mitogen-activated protein kinase are associated with their activation. Researches on the molecular mechanisms and signaling pathways of the DR will promote controlling the DR progression at the cellular level.

Citation： Li Shufeng, Hu Jianyan, Li Tingting, Wu Qiang. The current status and progress of the pathological changes and related molecular mechanisms of neuroretinal injury in diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2017, 33(3): 312-315. doi: 10.3760/cma.j.issn.1005-1015.2017.03.025 Copy

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2.	Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue[J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 789-794.
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9.	Semeraro F, Cancarini A, dell'Omo R, et al. Diabetic retinopathy: vascular and inflammatory disease[J/OL]. J Diabetes Res, 2015, 2015: 582060[2015-06-07]. . DOI: 10.1155/2015/582060.
10.	Tang J, Kern TS.Inflammation in diabetic retinopathy[J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
11.	Costa GN, Vindeirinho J, Cavadas C, et al. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose[J]. Mol Cell Neurosci, 2012, 50(1): 113-123. DOI: 10.1016/j.mcn.2012.04.003.
12.	Nakamura M, Barber AJ, Antonetti DA, et al. Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons[J]. J Biol Chem, 2001, 276(47): 43748-43755. DOI: 10.1074/jbc.M108594200.
13.	Ola MS, Nawaz MI, Siddiquei MM, et al. Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy[J]. J Diabetes Complications, 2012, 26(1): 56-64. DOI: 10.1016/j.jdiacomp.2011.11.004.
14.	Kowluru RA, Koppolu P, Chakrabarti S, et al. Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants[J]. Free Radic Res, 2003, 37(11): 1169-1180.
15.	Sasaki M, Ozawa Y, Kurihara T, et al. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes[J]. Diabetologia, 2010, 53(5): 971-979. DOI: 10.1007/s00125-009-1655-6.
16.	Cao Y, Li X, Shi P, et al. Effects of L-carnitine on high glucose-induced oxidative stress in retinal ganglion cells[J]. Pharmacology, 2014, 94(3-4): 123-130. DOI: 10.1159/000363062.
17.	Shimazawa M, Inokuchi Y, Ito Y, et al. Involvement of ER stress in retinal cell death[J]. Mol Vis, 2007, 13: 578-587.
18.	Sano R, Reed JC.ER stress-induced cell death mechanisms[J]. Biochim Biophys Acta, 2013, 1833(12): 3460-3470. DOI: 10.1016/j.bbamcr.2013.06.028.
19.	Villarroel M, Ciudin A, Hernández C, et al. Neurodegeneration: An early event of diabetic retinopathy[J]. World J Diabetes, 2010, 1(2): 57-64. DOI: 10.4239/wjd.v1.i2.57.
20.	Kurihara T, Ozawa Y, Shinoda K, et al. Neuroprotective effects of angiotensin Ⅱtype 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation[J]. Invest Ophthalmol Vis Sci, 2006, 47(12): 5545-5552.
21.	Santos-Carvalho A, Elvas F, Alvaro AR, et al. Neuropeptide Y receptors activation protects rat retinal neural cells against necrotic and apoptotic cell death induced by glutamate[J/OL]. Cell Death Dis, 2013, 4: E636[2013-05-16]. . DOI: 10.1038/cddis.2013.160. [published online aheda of print].
22.	Asomugha CO, Linn DM, Linn CL.ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs[J]. J Neurochem, 2010, 112(1): 214-226. DOI: 10.1111/j.1471-4159.2009.06447.x.
23.	Karsli-Uzunbas G, Guo JY, Price S, et al. Autophagy is required for glucose homeostasis and lung tumor maintenance[J]. Cancer Discov, 2014, 4(8): 914-927. DOI: 10.1158/2159-8290.CD-14-0363.
24.	Boya P, Esteban-Martinez L, Serrano-Puebla A, et al. Autophagy in the eye: Development, degeneration, and aging[J]. Prog Retin Eye Res, 2016, 55: 206-245. DOI: 10.1016/j.preteyeres.2016.08.001.
25.	Levine B, Kroemer G.Autophagy in the pathogenesis of disease[J]. Cell, 2008, 132(1): 27-42. DOI: 10.1016/j.cell.2007.12.018.
26.	Lin WJ, Kuang HY.Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells[J]. Autophagy, 2014, 10(10): 1692-1701.
27.	Rubinsztein DC, Mariño G, Kroemer G.Autophagy and aging[J]. Cell, 2011, 146(5): 682-695. DOI: 10.1016/j.cell.2011.07.030.
28.	Avruch J, Long X, Lin Y, et al. Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor[J]. Biochem Soc Trans, 2009, 37(Pt 1): 223-226. DOI: 10.1042/BST0370223.
29.	Poels J, Spasić MR, Callaerts P, et al. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy[J]. Bioessays, 2009, 31(9): 944-952. DOI: 10.1002/bies.200900003.
30.	Sundar Rajan S, Srinivasan V, Balasubramanyam M, et al. Endoplasmic reticulum (ER) stress & diabetes[J]. Indian J Med Res, 2007, 125(3): 411-424.
31.	Ding Y, Choi ME.Autophagy in diabetic nephropathy[J]. J Endocrinol, 2015, 224(1): 15-30. DOI: 10.1530/JOE-14-0437.
32.	Ma JH, Wang JJ, Zhang SX.The unfolded protein response and diabetic retinopathy[J/OL]. J Diabetes Res, 2014, 2014: 160140[2014-10-29]. . DOI: 10.1155/2014/160140.
33.	Ron D, Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
34.	Kroemer G, Mariño G, Levine B.Autophagy and the integrated stress response[J]. Mol Cell, 2010, 40(2): 280-293. DOI: 10.1016/j.molcel.2010.09.023.
35.	Curtis TM, Gardiner TA, Stitt AW.Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?[J]. Eye (Lond), 2009, 23(7): 1496-1508. DOI: 10.1038/eye.2009.108.
36.	Kitaoka Y, Munemasa Y, Kojima K, et al. Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration[J/OL]. Cell Death Dis, 2013, 4: E860[2013-10-17]. . DOI: 10.1038/cddis.2013.391. [published online aheda of print].
37.	Bringmann A, Iandiev I, Pannicke T, et al. Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects[J]. Prog Retin Eye Res, 2009, 28(6): 423-451. DOI: 10.1016/j.preteyeres.2009.07.001.
38.	Baydas G, Tuzcu M, Yasar A, et al. Early changes in glial reactivity and lipid peroxidation in diabetic rat retina: effects of melatonin[J]. Acta Diabetol, 2004, 41(3): 123-128.
39.	Asnaghi V, Gerhardinger C, Hoehn T, et al. A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat[J]. Diabetes, 2003, 52(2): 506-511.
40.	Nakazawa T, Shimura M, Ryu M, et al. ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury[J]. J Neurosci Res, 2008, 86(1): 136-144. [42]Sofroniew MV.Reactive astrocytes in neural repair and protection[J]. Neuroscientist, 2005, 11(5): 400-407.
41.	Sofroniew MV.Reactive astrocytes in neural repair and protection[J]. Neuroscientist,2005,11(5):400-407.
42.	Sorrentino FS, Allkabes M, Salsini G, et al. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy[J]. Life Sci, 2016, 162: 54-59. DOI: 10.1016/j.lfs.2016.08.001.
43.	Ibrahim AS, El-Remessy AB, Matragoon S, et al. Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes[J]. Diabetes, 2011, 60(4): 1122-1133. DOI: 10.2337/db10-1160.

1. Park SH, Park JW, Park SJ, et al. Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina[J]. Diabetologia, 2003, 46(9): 1260-1268.
2. Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue[J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 789-794.
3. Shi H, Zhang Z, Wang X, et al. Inhibition of autophagy induces IL-1β release from ARPE-19 cells via ROS mediated NLRP3 inflammasome activation under high glucose stress[J]. Biochem Biophys Res Commun, 2015, 463(4): 1071-1076. DOI: 10.1016/j.bbrc.2015.06.060.
4. Safi SZ, Qvist R, Kumar S, et al. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets[J/OL]. Biomed Res Int, 2014, 2014: 801269[2014-07-06]. . DOI: 10.1155/2014/801269.
5. Stem MS, Gardner TW.Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications[J]. Curr Med Chem, 2013, 20(26): 3241-3250.
6. Eisenberg-Lerner A, Bialik S, Simon HU, et al. Life and death partners: apoptosis, autophagy and the cross-talk between them[J]. Cell Death Differ, 2009, 16(7): 966-975. DOI: 10.1038/cdd.2009.33.
7. Golstein P, Kroemer G. Cell death by necrosis: towards a molecular definition[J]. Trends Biochem Sci, 2007, 32(1): 37-43. DOI: 10.1016/j.tibs.2006.11.001.
8. Pelikánová T.Pathogenesis of diabetic retinopathy[J]. Vnitr Lek, 2007, 53(5): 498-505.
9. Semeraro F, Cancarini A, dell'Omo R, et al. Diabetic retinopathy: vascular and inflammatory disease[J/OL]. J Diabetes Res, 2015, 2015: 582060[2015-06-07]. . DOI: 10.1155/2015/582060.
10. Tang J, Kern TS.Inflammation in diabetic retinopathy[J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
11. Costa GN, Vindeirinho J, Cavadas C, et al. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose[J]. Mol Cell Neurosci, 2012, 50(1): 113-123. DOI: 10.1016/j.mcn.2012.04.003.
12. Nakamura M, Barber AJ, Antonetti DA, et al. Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons[J]. J Biol Chem, 2001, 276(47): 43748-43755. DOI: 10.1074/jbc.M108594200.
13. Ola MS, Nawaz MI, Siddiquei MM, et al. Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy[J]. J Diabetes Complications, 2012, 26(1): 56-64. DOI: 10.1016/j.jdiacomp.2011.11.004.
14. Kowluru RA, Koppolu P, Chakrabarti S, et al. Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants[J]. Free Radic Res, 2003, 37(11): 1169-1180.
15. Sasaki M, Ozawa Y, Kurihara T, et al. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes[J]. Diabetologia, 2010, 53(5): 971-979. DOI: 10.1007/s00125-009-1655-6.
16. Cao Y, Li X, Shi P, et al. Effects of L-carnitine on high glucose-induced oxidative stress in retinal ganglion cells[J]. Pharmacology, 2014, 94(3-4): 123-130. DOI: 10.1159/000363062.
17. Shimazawa M, Inokuchi Y, Ito Y, et al. Involvement of ER stress in retinal cell death[J]. Mol Vis, 2007, 13: 578-587.
18. Sano R, Reed JC.ER stress-induced cell death mechanisms[J]. Biochim Biophys Acta, 2013, 1833(12): 3460-3470. DOI: 10.1016/j.bbamcr.2013.06.028.
19. Villarroel M, Ciudin A, Hernández C, et al. Neurodegeneration: An early event of diabetic retinopathy[J]. World J Diabetes, 2010, 1(2): 57-64. DOI: 10.4239/wjd.v1.i2.57.
20. Kurihara T, Ozawa Y, Shinoda K, et al. Neuroprotective effects of angiotensin Ⅱtype 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation[J]. Invest Ophthalmol Vis Sci, 2006, 47(12): 5545-5552.
21. Santos-Carvalho A, Elvas F, Alvaro AR, et al. Neuropeptide Y receptors activation protects rat retinal neural cells against necrotic and apoptotic cell death induced by glutamate[J/OL]. Cell Death Dis, 2013, 4: E636[2013-05-16]. . DOI: 10.1038/cddis.2013.160. [published online aheda of print].
22. Asomugha CO, Linn DM, Linn CL.ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs[J]. J Neurochem, 2010, 112(1): 214-226. DOI: 10.1111/j.1471-4159.2009.06447.x.
23. Karsli-Uzunbas G, Guo JY, Price S, et al. Autophagy is required for glucose homeostasis and lung tumor maintenance[J]. Cancer Discov, 2014, 4(8): 914-927. DOI: 10.1158/2159-8290.CD-14-0363.
24. Boya P, Esteban-Martinez L, Serrano-Puebla A, et al. Autophagy in the eye: Development, degeneration, and aging[J]. Prog Retin Eye Res, 2016, 55: 206-245. DOI: 10.1016/j.preteyeres.2016.08.001.
25. Levine B, Kroemer G.Autophagy in the pathogenesis of disease[J]. Cell, 2008, 132(1): 27-42. DOI: 10.1016/j.cell.2007.12.018.
26. Lin WJ, Kuang HY.Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells[J]. Autophagy, 2014, 10(10): 1692-1701.
27. Rubinsztein DC, Mariño G, Kroemer G.Autophagy and aging[J]. Cell, 2011, 146(5): 682-695. DOI: 10.1016/j.cell.2011.07.030.
28. Avruch J, Long X, Lin Y, et al. Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor[J]. Biochem Soc Trans, 2009, 37(Pt 1): 223-226. DOI: 10.1042/BST0370223.
29. Poels J, Spasić MR, Callaerts P, et al. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy[J]. Bioessays, 2009, 31(9): 944-952. DOI: 10.1002/bies.200900003.
30. Sundar Rajan S, Srinivasan V, Balasubramanyam M, et al. Endoplasmic reticulum (ER) stress & diabetes[J]. Indian J Med Res, 2007, 125(3): 411-424.
31. Ding Y, Choi ME.Autophagy in diabetic nephropathy[J]. J Endocrinol, 2015, 224(1): 15-30. DOI: 10.1530/JOE-14-0437.
32. Ma JH, Wang JJ, Zhang SX.The unfolded protein response and diabetic retinopathy[J/OL]. J Diabetes Res, 2014, 2014: 160140[2014-10-29]. . DOI: 10.1155/2014/160140.
33. Ron D, Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
34. Kroemer G, Mariño G, Levine B.Autophagy and the integrated stress response[J]. Mol Cell, 2010, 40(2): 280-293. DOI: 10.1016/j.molcel.2010.09.023.
35. Curtis TM, Gardiner TA, Stitt AW.Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?[J]. Eye (Lond), 2009, 23(7): 1496-1508. DOI: 10.1038/eye.2009.108.
36. Kitaoka Y, Munemasa Y, Kojima K, et al. Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration[J/OL]. Cell Death Dis, 2013, 4: E860[2013-10-17]. . DOI: 10.1038/cddis.2013.391. [published online aheda of print].
37. Bringmann A, Iandiev I, Pannicke T, et al. Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects[J]. Prog Retin Eye Res, 2009, 28(6): 423-451. DOI: 10.1016/j.preteyeres.2009.07.001.
38. Baydas G, Tuzcu M, Yasar A, et al. Early changes in glial reactivity and lipid peroxidation in diabetic rat retina: effects of melatonin[J]. Acta Diabetol, 2004, 41(3): 123-128.
39. Asnaghi V, Gerhardinger C, Hoehn T, et al. A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat[J]. Diabetes, 2003, 52(2): 506-511.
40. Nakazawa T, Shimura M, Ryu M, et al. ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury[J]. J Neurosci Res, 2008, 86(1): 136-144. [42]Sofroniew MV.Reactive astrocytes in neural repair and protection[J]. Neuroscientist, 2005, 11(5): 400-407.
41. Sofroniew MV.Reactive astrocytes in neural repair and protection[J]. Neuroscientist,2005,11(5):400-407.
42. Sorrentino FS, Allkabes M, Salsini G, et al. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy[J]. Life Sci, 2016, 162: 54-59. DOI: 10.1016/j.lfs.2016.08.001.
43. Ibrahim AS, El-Remessy AB, Matragoon S, et al. Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes[J]. Diabetes, 2011, 60(4): 1122-1133. DOI: 10.2337/db10-1160.

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