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Photoreceptor responses to light in the pathogenesis of diabetic retinopathy

Published online by Cambridge University Press:  14 September 2020

Shahriyar P. Majidi Open the ORCID record for Shahriyar P. Majidi [Opens in a new window]  and
Rithwick Rajagopal Open the ORCID record for Rithwick Rajagopal [Opens in a new window]
Shahriyar P. Majidi
Affiliation:
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri MD-PhD Program, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
Rithwick Rajagopal*
Affiliation:
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri
*
Address correspondence to: Rithwick Rajagopal, E-mail: [email protected]
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Abstract

Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic microvascular lesions. The reasons for retinal susceptibility to damage in diabetes are unclear, especially considering that microvascular networks are found in all tissues. However, the unique metabolic demands of retinal neurons could account for their vulnerability in diabetes. Photoreceptors are the first neurons in the visual circuit and are also the most energy-demanding cells of the retina. Here, we review experimental and clinical evidence linking photoreceptors to the development of diabetic retinopathy. We then describe the influence of retinal illumination on photoreceptor metabolism, effects of light modulation on the severity of diabetic retinopathy, and recent clinical trials testing the treatment of diabetic retinopathy with interventions that impact photoreceptor metabolism. Finally, we introduce several possible mechanisms that could link photoreceptor responses to light and the development of retinal vascular disease in diabetes. Collectively, these concepts form the basis for a growing body of investigative efforts aimed at developing novel pharmacologic and nonpharmacologic tools that target photoreceptor physiology to treat a very common cause of blindness across the world.

Keywords

Diabetic retinopathyphotoreceptormetabolismphototransductionlight deprivationvisual cycle
Type
Review Article
Information
Visual Neuroscience , Volume 37 , 2020 , E007
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Copyright
© The Author(s), 2020. Published by Cambridge University Press

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References

Adler, L.T., Chen, C. & Koutalos, Y. (2014). Mitochondria contribute to NADPH generation in mouse rod photoreceptors. Journal of Biological Chemistry 289, 1519–1528.CrossRefGoogle ScholarPubMed
Anderson, G.R., Posokhova, E. & Martemyanov, K.A. (2009). The R7 RGS protein family: Multi-subunit regulators of neuronal G protein signaling. Cell Biochemistry and Biophysics 54, 33–46.CrossRefGoogle ScholarPubMed
Antonetti, D.A., Barber, A.J., Bronson, S.K., Freeman, W.M., Gardner, T.W., Jefferson, L.S., Kester, M., Kimball, S.R., Krady, J.K., Lanoue, K.F., Norbury, C.C., Quinn, P.G., Sandirasegarane, L., Simpson, I.A. & Group, J.D.R.C. (2006). Diabetic retinopathy: Seeing beyond glucose-induced microvascular disease. Diabetes 55, 2401–2411.CrossRefGoogle ScholarPubMed
Arden, G.B. (2001). The absence of diabetic retinopathy in patients with retinitis pigmentosa: Implications for pathophysiology and possible treatment. British Journal of Ophthalmology 85, 366–370.CrossRefGoogle ScholarPubMed
Arden, G.B., Gunduz, M.K., Kurtenbach, A., Volker, M., Zrenner, E., Gunduz, S.B., Kamis, U., Ozturk, B.T. & Okudan, S. (2010). A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy. Eye (Lond) 24, 1149–1155.CrossRefGoogle ScholarPubMed
Arden, G.B., Jyothi, S., Hogg, C.H., Lee, Y.F. & Sivaprasad, S. (2011). Regression of early diabetic macular oedema is associated with prevention of dark adaptation. Eye (London) 25, 1546–1554.CrossRefGoogle ScholarPubMed
Arden, G.B., Sidman, R.L., Arap, W. & Schlingemann, R.O. (2005). Spare the rod and spoil the eye. British Journal of Ophthalmology 89, 764–769.CrossRefGoogle ScholarPubMed
Arshavsky, V.Y. & Burns, M.E. (2012). Photoreceptor signaling: Supporting vision across a wide range of light intensities. Journal of Biological Chemistry 287, 1620–1626.CrossRefGoogle ScholarPubMed
Arshavsky, V.Y., Lamb, T.D. & Pugh, E.N. (2002). G proteins and phototransduction. Annual Review of Physiology 64, 153–187.CrossRefGoogle ScholarPubMed
Benedetto, M.M. & Contin, M.A. (2019). Oxidative stress in retinal degeneration promoted by constant LED light. Frontiers in Cellular Neuroscience 13, 139.CrossRefGoogle ScholarPubMed
Berkowitz, B.A., Grady, E.M., Khetarpal, N., Patel, A. & Roberts, R. (2015). Oxidative stress and light-evoked responses of the posterior segment in a mouse model of diabetic retinopathy. Investigative Ophthalmology and Visual Science 56, 606–615.CrossRefGoogle Scholar
Braun, R.D., Linsenmeier, R.A. & Goldstick, T.K. (1995). Oxygen consumption in the inner and outer retina of the cat. Investigative Ophthalmology and Visual Science 36, 542–554.Google ScholarPubMed
Bresnick, G.H. & Palta, M. (1987). Temporal aspects of the electroretinogram in diabetic retinopathy. Archives of Ophthalmology 105, 660–664.CrossRefGoogle ScholarPubMed
Calvert, P.D., Strissel, K.J., Schiesser, W.E., Pugh, E.N. & Arshavsky, V.Y. (2006). Light-driven translocation of signaling proteins in vertebrate photoreceptors. Trends in Cell Biology 16, 560–568.CrossRefGoogle ScholarPubMed
Chen, Y., Y., Hu, Lin, M., Jenkins, A.J., Keech, A.C., Mott, R., Lyons, T.J. & Ma, J.X. (2013). Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models. Diabetes 62, 261–272.CrossRefGoogle ScholarPubMed
Curcio, C.A., Sloan, K.R., Kalina, R.E. & Hendrickson, A.E. (1990). Human photoreceptor topography. Journal of Comparative Neurology 292, 497–523.CrossRefGoogle ScholarPubMed
De Gooyer, T.E., Stevenson, K.A., Humphries, P., Simpson, D.A., Curtis, T.M., Gardiner, T.A. & Stitt, A.W. (2006a). Rod photoreceptor loss in Rho−/− mice reduces retinal hypoxia and hypoxia-regulated gene expression. Investigative Ophthalmology and Visual Science 47, 5553–5560.CrossRefGoogle Scholar
De Gooyer, T.E., Stevenson, K.A., Humphries, P., Simpson, D.A., Gardiner, T.A. & Stitt, A.W. (2006b). Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Investigative Ophthalmology and Visual Science 47, 5561–5568.CrossRefGoogle Scholar
Dean, F.M., Arden, G.B. & Dornhorst, A. (1997). Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects. British Journal of Ophthalmology 81, 27–30.CrossRefGoogle ScholarPubMed
Drasdo, N., Chiti, Z., Owens, D.R. & North, R.V. (2002). Effect of darkness on inner retinal hypoxia in diabetes. Lancet 359, 2251–2253.CrossRefGoogle ScholarPubMed
Du, J., Rountree, A., Cleghorn, W.M., Contreras, L., Lindsay, K.J., Sadilek, M., Gu, H., Djukovic, D., Raftery, D., Satrustegui, J., Kanow, M., Chan, L., Tsang, S.H., Sweet, I.R. & Hurley, J.B. (2016). Phototransduction influences metabolic flux and nucleotide metabolism in mouse retina. Journal of Biological Chemistry 291, 4698–4710.CrossRefGoogle ScholarPubMed
Du, Y., Veenstra, A., Palczewski, K. & Kern, T.S. (2013). Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proceedings of the National Academy of Sciences of the United States of America 110, 16586–16591.CrossRefGoogle ScholarPubMed
Elsner, A.E., Burns, S.A., Lobes, L.A. & Doft, B.H. (1987). Cone photopigment bleaching abnormalities in diabetes. Investigative Ophthalmology and Visual Science 28, 718–724.Google ScholarPubMed
Fain, G.L., Matthews, H.R. & Cornwall, M.C. (1996). Dark adaptation in vertebrate photoreceptors. Trends in Neurosciences 19, 502–507.CrossRefGoogle ScholarPubMed
Fu, Z., Kern, T.S., Hellstrom, A. & Smith, L. (2020). Fatty acid oxidation and photoreceptor metabolic needs. Journal of Lipid Research. 61(2)Google Scholar
Glancy, B. & Balaban, R.S. (2012). Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51, 2959–2973.CrossRefGoogle ScholarPubMed
Graham, C.E., Binz, N., Shen, W.Y., Constable, I.J. & Rakoczy, E.P. (2006). Laser photocoagulation: Ocular research and therapy in diabetic retinopathy. Advances in Experimental Medicine and Biology 572, 195–200.CrossRefGoogle ScholarPubMed
Group, A.S., Group, A.E.S., Chew, E.Y., Ambrosius, W.T., Davis, M.D., Danis, R.P., Gangaputra, S. , Greven, C.M., Hubbard, L., Esser, B.A., Lovato, J.F., Perdue, L.H., Goff, D.C., Cushman, W.C., Ginsberg, H.N., Elam, M.B., Genuth, S., Gerstein, H.C., Schubart, U. & Fine, L.J. (2010). Effects of medical therapies on retinopathy progression in type 2 diabetes. New England Journal of Medicine 363, 233–244.Google Scholar
Habib, N.A., Wood, C.B., Apostolov, K., Barker, W., Hershman, M.J., Aslam, M., Heinemann, D., Fermor, B., Williamson, R.C., Jenkins, W.E. (1987). Stearic acid and carcinogenesis. British Journal of Cancer 56, 455–458.CrossRefGoogle ScholarPubMed
Hagins, W.A., Penn, R.D. & Yoshikami, S. (1970). Dark current and photocurrent in retinal rods. Biophysical Journal 10, 380–412.CrossRefGoogle ScholarPubMed
Hargrave, P.A. (2001). Rhodopsin structure, function, and topography the Friedenwald lecture. Investigative Ophthalmology and Visual Science 42, 3–9.Google ScholarPubMed
Harris, A., Arend, O., Danis, R.P., Evans, D., Wolf, S. & Martin, B.J. (1996). Hyperoxia improves contrast sensitivity in early diabetic retinopathy. British Journal of Ophthalmology 80, 209–213.CrossRefGoogle ScholarPubMed
Holopigian, K., Greenstein, V.C., Seiple, W., Hood, D.C. & Carr, R.E. (1997). Evidence for photoreceptor changes in patients with diabetic retinopathy. Investigative Ophthalmology and Visual Science 38, 2355–2365.Google ScholarPubMed
Honasoge, A., Nudleman, E., Smith, M. & Rajagopal, R. (2019). Emerging insights and interventions for diabetic retinopathy. Current Diabetes Reports 19, 100.CrossRefGoogle ScholarPubMed
Investigators (1978). Photocoagulation treatment of proliferative diabetic retinopathy: The second report of diabetic retinopathy study findings. Ophthalmology 85, 82–106.CrossRefGoogle Scholar
Joyal, J.S., Gantner, M.L. & Smith, L.E.H. (2018). Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Progress in Retinal and Eye Research 64, 131–156.CrossRefGoogle ScholarPubMed
Joyal, J.S., Sun, Y., Gantner, M.L., Shao, Z., Evans, L.P., Saba, N., Fredrick, T., Burnim, S., Kim, J.S., Patel, G., Juan, A.M., Hurst, C.G., Hatton, C.J., Cui, Z., Pierce, K.A., Bherer, P., Aguilar, E., Powner, M.B., Vevis, K., Boisvert, M., Z, Fu., Levy, E., Fruttiger, M., Packard, A., Rezende, F.A., Maranda, B., Sapieha, P., Chen, J., Friedlander, M., Clish, C. B. & Smith, L.E. (2016). Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nature Medicine 22, 439–445.CrossRefGoogle ScholarPubMed
Keech, A.C., Mitchell, P., Summanen, P.A., O’day, J., Davis, T.M., Moffitt, M.S., Taskinen, M.R., Simes, R.J., Tse, D., Williamson, E., Merrifield, A., Laatikainen, L.T., D’emden, M.C., Crimet, D.C., O’connell, R.L., Colman, P.G. & Investigators, F.S. (2007). Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): A randomised controlled trial. Lancet 370, 1687–1697.CrossRefGoogle ScholarPubMed
Kefalov, V.J. (2012). Rod and cone visual pigments and phototransduction through pharmacological, genetic, and physiological approaches. Journal of Biological Chemistry 287, 1635–1641.CrossRefGoogle ScholarPubMed
Kern, T.S. (2017). Do photoreceptor cells cause the development of retinal vascular disease? Vision Research 139, 65–71.CrossRefGoogle ScholarPubMed
Krizaj, D. & Copenhagen, D.R. (2002). Calcium regulation in photoreceptors. Frontiers in Bioscience 7, d2023–2044.CrossRefGoogle ScholarPubMed
Kubota, R., Al-Fayoumi, S., Mallikaarjun, S., Patil, S., Bavik, C. & Chandler, J.W. (2014). Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina 34, 603–609.CrossRefGoogle Scholar
Kubota, R., Calkins, D.J., Henry, S.H. & Linsenmeier, R.A. (2019). Emixustat reduces metabolic demand of dark activity in the retina. Investigative Ophthalmology and Visual Science 60 ,4924–4930.CrossRefGoogle ScholarPubMed
Kubota, R., Gregory, J., Henry, S. & Mata, N.L. (2020). Pharmacotherapy for metabolic and cellular stress in degenerative retinal diseases. Drug Discovery Today 25, 292–304.CrossRefGoogle ScholarPubMed
Kur, J., Burian, M.A. & Newman, E.A. (2016). Light adaptation does not prevent early retinal abnormalities in diabetic rats. Scientific Reports 6, 21075.CrossRefGoogle Scholar
Linsenmeier, R.A. (1986). Effects of light and darkness on oxygen distribution and consumption in the cat retina. Journal of General Physiology 88 ,521–542.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 and Visual Science 60, 1538–1546.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Du, Y., Saadane, A., Tonade, D., Samuels, I., Veenstra, A., Palczewski, K. & Kern, T.S. (2016). Photoreceptor cells influence retinal vascular degeneration in mouse models of retinal degeneration and diabetes. Investigative Ophthalmology and Visual Science 57, 4272–4281.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Y, Du., 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, 21568–21579.CrossRefGoogle ScholarPubMed
Liu, W., Wang, S., Soetikno, B., Yi, J., Zhang, K., Chen, S., Linsenmeier, R.A., Sorenson, C.M., Sheibani, N. & Zhang, H.F. (2017). Increased retinal oxygen metabolism precedes microvascular alterations in type 1 diabetic mice. Investigative Ophthalmology and Visual Science 58, 981–989.CrossRefGoogle ScholarPubMed
Llorente-Folch, I., Rueda, C.B., Pardo, B., Szabadkai, G., Duchen, M.R. & Satrustegui, J. (2015). The regulation of neuronal mitochondrial metabolism by calcium. Journal of Physiology 593, 3447–3462.CrossRefGoogle ScholarPubMed
Mcanany, J.J. & Park, J.C. (2019). Cone photoreceptor dysfunction in early-stage diabetic retinopathy: Association between the activation phase of cone phototransduction and the flicker electroretinogram. Investigative Ophthalmology and Visual Science 60, 64–72.CrossRefGoogle ScholarPubMed
Mendez, A., Burns, M.E., Roca, A., Lem, J., Wu, L.W., Simon, M.I., Baylor, D.A. & Chen, J. (2000). Rapid and reproducible deactivation of rhodopsin requires multiple phosphorylation sites. Neuron 28, 153–164.CrossRefGoogle ScholarPubMed
Meinild lundby, A. K., Jacobs, R. A., Gehrig, S., De Leur, J., Hauser, M., Bonne, T. C., Fluck, D., Dandanell, S., Kirk, N., Kaech, A., Ziegler, U., Larsen, S. & LUNDBY, C. 2018. Exercise training increases skeletal muscle mitochondrial volume density by enlargement of existing mitochondria and not de novo biogenesis. Acta Physiol (Oxf), 222.CrossRefGoogle Scholar
Metea, M.R. & Newman, E.A. (2006). Glial cells dilate and constrict blood vessels: A mechanism of neurovascular coupling. Journal of Neuroscience 26, 2862–2870.CrossRefGoogle ScholarPubMed
Mishra, A. & Newman, E.A. (2010). Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58, 1996–2004.CrossRefGoogle ScholarPubMed
Mishra, A. & Newman, E.A. (2011). Aminoguanidine reverses the loss of functional hyperemia in a rat model of diabetic retinopathy. Front Neuroenergetics 3, 10.Google Scholar
Newman, E.A. (2013). Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. Journal of Cerebral Blood Flow and Metabolism 33 ,1685–1695.CrossRefGoogle ScholarPubMed
Okada, M. & Chhablani, J. (2018). Out of darkness comes light-is there a role for light masks in treatment of diabetic macular oedema? Annals of Translational Medicine 6, S73.CrossRefGoogle Scholar
Okawa, H., Sampath, A. P., Laughlin, S.B. & Fain, G.L. (2008). ATP consumption by mammalian rod photoreceptors in darkness and in light. Current Biology 18, 1917–1921.CrossRefGoogle ScholarPubMed
Reiter, C. E., Wu, X., Sandirasegarane, L., Nakamura, M., Gilbert, K. A., Singh, R. S., Fort, P. E., Antonetti, D. A. & Gardner, T. W. 2006. Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin. Diabetes, 55, 1148–56.CrossRefGoogle ScholarPubMed
Saari, J.C. (2000). Biochemistry of visual pigment regeneration: The Friedenwald lecture. Investigative Ophthalmology and Visual Science 41, 337–348.Google ScholarPubMed
Sakami, S., Maeda, T., Bereta, G., Okano, K., Golczak, M., Sumaroka, A., Roman, A.J., Cideciyan, A.V., Jacobson, S.G. & Palczewski, K. (2011). Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. Journal of Biological Chemistry 286, 10551–10567.CrossRefGoogle Scholar
Scarinci, F., Jampol, L.M., Linsenmeier, R.A. & Fawzi, A.A. (2015). Association of diabetic macular nonperfusion with outer retinal disruption on optical coherence tomography. JAMA Ophthalmology 133 ,1036–1044.CrossRefGoogle ScholarPubMed
Scarinci, F., Nesper, P.L. & Fawzi, A.A. (2016). Deep retinal capillary nonperfusion is associated with photoreceptor disruption in diabetic macular ischemia. American Journal of Ophthalmology 168, 129–138.CrossRefGoogle ScholarPubMed
Sivaprasad, S., Vasconcelos, J.C., Prevost, A.T., Holmes, H., Hykin, P., George, S., Murphy, C., Kelly, J., Arden, G.B. & Group, C.S. (2018). Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): A multicentre, phase 3, randomised controlled trial. The Lancet Diabetes & Endocrinology 6, 382–391.CrossRefGoogle ScholarPubMed
Stephen, R., Filipek, S., Palczewski, K. & Sousa, M.C. (2008). Ca2+ − dependent regulation of phototransduction. Photochemistry and Photobiology 84, 903–910.CrossRefGoogle ScholarPubMed
Sternberg, P., Landers, M.B. & Wolbarsht, M. (1984). The negative coincidence of retinitis pigmentosa and proliferative diabetic retinopathy. American Journal of Ophthalmology 97, 788–789.CrossRefGoogle ScholarPubMed
Thebeau, C., Zhang, S., Kolesnikov, A.V., Kefalov, V.J., Semenkovich, C.F. & Rajagopal, R. (2020). Light deprivation reduces the severity of experimental diabetic retinopathy. Neurobiology of Disease 137, 104754.CrossRefGoogle ScholarPubMed
Wang, L., Tornquist, P. & Bill, A. (1997). Glucose metabolism in pig outer retina in light and darkness. Acta Physiologica Scandinavica 160, 75–81.CrossRefGoogle Scholar
Warburg, O., Wind, F. & Negelein, E. (1927). The metabolism of tumors in the body. Journal of General Physiology 8 ,519–530.CrossRefGoogle Scholar
Wong-Riley, M.T. (2010). Energy metabolism of the visual system. Eye Brain 2 ,99–116.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 49.CrossRefGoogle ScholarPubMed