Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-04T21:17:24.088Z Has data issue: false hasContentIssue false

The neuroscience of diabetic retinopathy

Published online by Cambridge University Press:  18 January 2021

David A. Antonetti*
Affiliation:
Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
*
Address correspondence to: David A. Antonetti, E-mail: [email protected]

Abstract

Diabetic retinopathy remains a leading cause of blindness despite recent advance in therapies. Traditionally, this complication of diabetes was viewed predominantly as a microvascular disease but research has pointed to alterations in ganglion cells, glia, microglia, and photoreceptors as well, often occurring without obvious vascular damage. In neural tissue, the microvasculature and neural tissue form an intimate relationship with the neural tissue providing signaling cues for the vessels to form a distinct barrier that helps to maintain the proper neuronal environment for synaptic signaling. This relationship has been termed the neurovascular unit (NVU). Research is now focused on understanding the cellular and molecular basis of the neurovascular unit and how diabetes alters the normal cellular communications and disrupts the cellular environment contributing to loss of vision in diabetes.

Type
Perspective
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ajlan, R.S., Silva, P.S. & Sun, J.K. (2016). Vascular endothelial growth factor and diabetic retinal disease. Seminars in Ophthalmology 31, 4048.CrossRefGoogle ScholarPubMed
Antonetti, D.A., Klein, R. & Gardner, T.W. (2012). Diabetic retinopathy. The New England Journal of Medicine 366, 12271239.CrossRefGoogle ScholarPubMed
Barber, A.J., Lieth, E., Khin, S.A., Antonetti, D.A., Buchanan, A.G. & Gardner, T.W. (1998). Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. Journal of Clinical Investigation 102, 783791.CrossRefGoogle ScholarPubMed
Boyle, J.P., Thompson, T.J., Gregg, E.W., Barker, L.E. & Williamson, D.F. (2010). Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Population Health Metrics 8, 29.CrossRefGoogle ScholarPubMed
Cerani, A., Tetreault, N., Menard, C., Lapalme, E., Patel, C., Sitaras, N., Beaudoin, F., Leboeuf, D., De Guire, V., Binet, F., Dejda, A., Rezende, F.A., Miloudi, K. & Sapieha, P. (2013). Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1. Cell Metabolism 18, 505518.CrossRefGoogle ScholarPubMed
Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. (2010). Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562566.CrossRefGoogle ScholarPubMed
Diaz-Coranguez, M., Lin, C.M., Liebner, S. & Antonetti, D.A. (2020). Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability. Journal of Biological Chemistry 295, 46474660.CrossRefGoogle ScholarPubMed
Early Treatment Diabetic Retinopathy Study Research Group (1991). Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 98, 786806.CrossRefGoogle Scholar
Fong, D.S., Aiello, L., Gardner, T.W., King, G.L., Blankenship, G., Cavallerano, J.D., Ferris, F.L. III, Klein, R. & American Diabetes, A. (2003). Diabetic retinopathy. Diabetes Care 26, 226229.CrossRefGoogle ScholarPubMed
Fu, Z., Sun, Y., Cakir, B., Tomita, Y., Huang, S., Wang, Z., Liu, C.H., Cho, S.S., Britton, W., Kern, S.T., Antonetti, D.A., Hellstrom, A. & Lois, E.H.S. (2020). Targeting neurovascular interaction in retinal disorders. International Journal of Molecular Sciences 21(4): 1503.CrossRefGoogle ScholarPubMed
Gardner, T.W., Abcouwer, S.F., Barber, A.J. & Jackson, G.R. (2011). An integrated approach to diabetic retinopathy research. Archives of Ophthalmology 129, 230235.CrossRefGoogle ScholarPubMed
Greene, C., Kealy, J., Humphries, M.M., Gong, Y., Hou, J., Hudson, N., Cassidy, L.M., Martiniano, R., Shashi, V., Hooper, S.R., Grant, G.A., Kenna, P.F., Norris, K., Callaghan, C.K., Islam, M.D., O’Mara, S.M., Najda, Z., Campbell, S.G., Pachter, J.S., Thomas, J., Williams, N.M., Humphries, P., Murphy, K.C. & Campbell, M. (2018). Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Molecular Psychiatry 23, 21562166.CrossRefGoogle Scholar
Iadecola, C. (2017). The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron 96, 1742.CrossRefGoogle ScholarPubMed
Klein, R., Klein, B.E., Moss, S.E. & Cruickshanks, K.J. (1998). The Wisconsin epidemiologic study of diabetic retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 105, 18011815.CrossRefGoogle ScholarPubMed
Li, A.S., Veerappan, M., Mittal, V. & Do, D.V. (2020). Anti-VEGF agents in the management of diabetic macular edema. Expert Review of Ophthalmology 15, 285296.CrossRefGoogle Scholar
Lindblom, P., Gerhardt, H., Liebner, S., Abramsson, A., Enge, M., Hellstrom, M., Backstrom, G., Fredriksson, S., Landegren, U., Nystrom, H.C., Bergstrom, G., Dejana, E., Ostman, A., Lindahl, P. & Betsholtz, C. (2003). Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes & Development 17, 18351840.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Du, Y., Lee, C.A., Golczak, M., Muthusamy, A., Antonetti, D.A., Veenstra, A.A., Amengual, J., von Lintig, J., Palczewski, K. & Kern, T.S. (2015). Retinylamine benefits early diabetic retinopathy in mice. Journal of Biological Chemistry 290, 2156821579.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Du, Y., Saadane, A., Samuels, I., Veenstra, A., Kiser, J.Z., Palczewski, K. & Kern, T.S. (2019). Transducin1, phototransduction and the development of early diabetic retinopathy. Investigative Ophthalmology & Visual Science 60, 15381546.CrossRefGoogle ScholarPubMed
Lynch, S.K. & Abramoff, M.D. (2017). Diabetic retinopathy is a neurodegenerative disorder. Vision Research 139, 101107.CrossRefGoogle ScholarPubMed
Moss, S.E., Klein, R. & Klein, B.E. (1998). The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105, 9981003.CrossRefGoogle Scholar
Ronald Klein, M.P.H., Knudtson, M.D., Lee, K.E.,Gangnon, R. & Klein, B.E.K. (2008). The Wisconsin epidemiologic study of diabetic retinopathy XXII. The twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008 Nov;115(11):1859–68CrossRefGoogle Scholar
Santos, A.R., Ribeiro, L., Bandello, F., Lattanzio, R., Egan, C., Frydkjaer-Olsen, U., Garcia-Arumi, J., Gibson, J., Grauslund, J., Harding, S.P., Lang, G.E., Massin, P., Midena, E., Scanlon, P., Aldington, S.J., Simao, S., Schwartz, C., Ponsati, B., Porta, M., Costa, M.A., Hernandez, C., Cunha-Vaz, J., Simo, R. & European Consortium for the Early Treatment of Diabetic R (2017). Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: Cross-sectional analyses of baseline data of the EUROCONDOR project. Diabetes 66, 25032510.CrossRefGoogle ScholarPubMed
Simo, R., Sundstrom, J.M. & Antonetti, D.A. (2014). Ocular anti-VEGF therapy for diabetic retinopathy: The role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care 37, 893899.CrossRefGoogle ScholarPubMed
Sohn, E.H., van Dijk, H.W., Jiao, C., Kok, P.H., Jeong, W., Demirkaya, N., Garmager, A., Wit, F., Kucukevcilioglu, M., van Velthoven, M.E., DeVries, J.H., Mullins, R.F., Kuehn, M.H., Schlingemann, R.O., Sonka, M., Verbraak, F.D. & Abramoff, M.D. (2016). Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 113, E2655E2664.CrossRefGoogle ScholarPubMed
Wang, Y., Rattner, A., Zhou, Y., Williams, J., Smallwood, P.M. & Nathans, J. (2012). Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 151, 13321344.CrossRefGoogle ScholarPubMed
Wei, Y., Gong, J., Xu, Z., Thimmulappa, R.K., Mitchell, K.L., Welsbie, D.S., Biswal, S. & Duh, E.J. (2015). Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Proceedings of National Academy of Sciences of the United States of America 112, E6927E6936.CrossRefGoogle ScholarPubMed
Wu, J.H., Li, Y.N., Chen, A.Q., Hong, C.D., Zhang, C.L., Wang, H.L., Zhou, Y.F., Li, P.C., Wang, Y., Mao, L., Xia, Y.P., He, Q.W., Jin, H.J., Yue, Z.Y. & Hu, B. (2020). Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy. EMBO Molecular Medicine 12, e10154.CrossRefGoogle ScholarPubMed
Yau, J.W., Rogers, S.L., Kawasaki, R., Lamoureux, E.L., Kowalski, J.W., Bek, T., Chen, S.J., Dekker, J.M., Fletcher, A., Grauslund, J., Haffner, S., Hamman, R.F., Ikram, M.K., Kayama, T., Klein, B.E., Klein, R., Krishnaiah, S., Mayurasakorn, K., O’Hare, J.P., Orchard, T.J., Porta, M., Rema, M., Roy, M.S., Sharma, T., Shaw, J., Taylor, H., Tielsch, J.M., Varma, R., Wang, J.J., Wang, N., West, S., Xu, L., Yasuda, M., Zhang, X., Mitchell, P., Wong, T.Y. & Meta-Analysis for Eye Disease Study G (2012). Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35, 556564.CrossRefGoogle ScholarPubMed
Yokomizo, H., Maeda, Y., Park, K., Clermont, A.C., Hernandez, S.L., Fickweiler, W., Li, Q., Wang, C.H., Paniagua, S.M., Simao, F., Ishikado, A., Sun, B., Wu, I.H., Katagiri, S., Pober, D.M., Tinsley, L.J., Avery, R.L., Feener, E.P., Kern, T.S., Keenan, H.A., Aiello, L.P., Sun, J.K. & King, G.L. (2019). Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy. Science Translational Medicine 11.CrossRefGoogle ScholarPubMed
Zhou, Y., Wang, Y., Tischfield, M., Williams, J., Smallwood, P.M., Rattner, A., Taketo, M.M. & Nathans, J. (2014). Canonical WNT signaling components in vascular development and barrier formation. Journal of Clinical Investigation 124, 38253846.CrossRefGoogle ScholarPubMed