Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Current understanding of the molecular and cellular pathology of diabetic retinopathy

Abstract

Diabetes mellitus has profound effects on multiple organ systems; however, the loss of vision caused by diabetic retinopathy might be one of the most impactful in a patient’s life. The retina is a highly metabolically active tissue that requires a complex interaction of cells, spanning light sensing photoreceptors to neurons that transfer the electrochemical signal to the brain with support by glia and vascular tissue. Neuronal function depends on a complex inter-dependency of retinal cells that includes the formation of a blood–retinal barrier. This dynamic system is negatively affected by diabetes mellitus, which alters normal cell–cell interactions and leads to profound vascular abnormalities, loss of the blood–retinal barrier and impaired neuronal function. Understanding the normal cell signalling interactions and how they are altered by diabetes mellitus has already led to novel therapies that have improved visual outcomes in many patients. Research highlighted in this Review has led to a new understanding of retinal pathophysiology during diabetes mellitus and has uncovered potential new therapeutic avenues to treat this debilitating disease.

Key points

  • Diabetic retinopathy is a leading cause of blindness that disrupts the normal interaction of the retinal neural and vascular components leading to vascular permeability, neovascularization and loss of proper neural function.

  • Current effective therapeutic approaches target vascular endothelial growth factor, while a host of new therapies targeting vascular endothelial and pericyte signalling and inflammatory cytokines are being tested for diabetic retinopathy.

  • Stem cell therapy for vascular regeneration holds potential for restorative therapeutic approaches in diabetic retinopathy.

  • Understanding the neuronal and glial changes that drive loss of vision is rapidly emerging, and targeted approaches to directly test the relationship between the neurovascular unit and alteration in diabetic retinopathy are needed.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Diabetic retinopathy manifests with multiple pathologies.
Fig. 2: The neurovascular unit and cytokine signalling in diabetic retinopathy.

References

  1. 1.

    Ogurtsova, K. et al. IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 128, 40–50 (2017).

    CAS  PubMed  Google Scholar 

  2. 2.

    Ajlan, R. S., Silva, P. S. & Sun, J. K. Vascular endothelial growth factor and diabetic retinal disease. Semin. Ophthalmol. 31, 40–48 (2016).

    PubMed  Google Scholar 

  3. 3.

    Li, A. S., Veerappan, M., Mittal, V. & Do, D. V. Anti-VEGF agents in the management of diabetic macular edema. Expert Rev. Ophthalmol. 15, 285–296 (2020).

    CAS  Google Scholar 

  4. 4.

    [No authors listed]. Grading diabetic retinopathy from stereoscopic color fundus photographs–an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98, 786–806 (1991).

    Google Scholar 

  5. 5.

    Solomon, S. D. et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 40, 412–418 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kohner, E. M., Patel, V. & Rassam, S. M. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes 44, 603–607 (1995).

    CAS  PubMed  Google Scholar 

  7. 7.

    Roy, S., Ha, J., Trudeau, K. & Beglova, E. Vascular basement membrane thickening in diabetic retinopathy. Curr. Eye Res. 35, 1045–1056 (2010).

    PubMed  Google Scholar 

  8. 8.

    Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    [No authors listed]. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98, 823–833 (1991).

    Google Scholar 

  10. 10.

    Klein, R. et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXII. The twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 115, 1859–1868 (2008).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Browning, D. J. et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology 114, 525–536 (2007).

    PubMed  Google Scholar 

  12. 12.

    Gardner, T. W., Larsen, M., Girach, A. & Zhi, X. Diabetic macular oedema and visual loss: relationship to location, severity and duration. Acta Ophthalmol. 87, 709–713 (2009).

    PubMed  Google Scholar 

  13. 13.

    [No authors listed]. Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch. Ophthalmol. 103, 1796–1806 (1985).

    Google Scholar 

  14. 14.

    Cunha-Vaz, J. Mechanisms of retinal fluid accumulation and blood-retinal barrier breakdown. Dev. Ophthalmol. 58, 11–20 (2017).

    PubMed  Google Scholar 

  15. 15.

    Samuels, I. S., Bell, B. A., Pereira, A., Saxon, J. & Peachey, N. S. Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes. J. Neurophysiol. 113, 1085–1099 (2015).

    CAS  PubMed  Google Scholar 

  16. 16.

    Bentley, K. et al. The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat. Cell Biol. 16, 309–321 (2014).

    CAS  PubMed  Google Scholar 

  17. 17.

    Desjardins, D. M. et al. Progressive early breakdown of retinal pigment epithelium function in hyperglycemic rats. Invest. Ophthalmol. Vis. Sci. 57, 2706–2713 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lutty, G. A. Effects of diabetes on the eye. Invest. Ophthalmol. Vis. Sci. 54, ORSF81–ORSF87 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wilkinson, C. P. et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110, 1677–1682 (2003).

    CAS  PubMed  Google Scholar 

  20. 20.

    Abramoff, M. D. et al. Approach for a clinically useful comprehensive classification of vascular and neural aspects of diabetic retinal disease. Invest. Ophthalmol. Vis. Sci. 59, 519–527 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Klein, B. E. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol. 14, 179–183 (2007).

    PubMed  Google Scholar 

  22. 22.

    Klein, R., Klein, B. E., Moss, S. E. & Cruickshanks, K. J. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology 102, 7–16 (1995).

    CAS  PubMed  Google Scholar 

  23. 23.

    Duh, E. J., Sun, J. K. & Stitt, A. W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2, e93751 (2017).

    PubMed Central  Google Scholar 

  24. 24.

    Klein, R. in Diabetic Retinopathy Ch. 3 (ed. Duh, E.) 67–107 (Humana, 2008).

  25. 25.

    Kady, N. M. et al. ELOVL4-mediated production of very long-chain ceramides stabilizes tight junctions and prevents diabetes-induced retinal vascular permeability. Diabetes 67, 769–781 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Tikhonenko, M. et al. Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes 59, 219–227 (2010).

    CAS  PubMed  Google Scholar 

  27. 27.

    Silva, P. S. et al. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology 120, 2587–2595 (2013).

    PubMed  Google Scholar 

  28. 28.

    Rasmussen, M. L. et al. Comparison between early treatment diabetic retinopathy study 7-field retinal photos and non-mydriatic, mydriatic and mydriatic steered widefield scanning laser ophthalmoscopy for assessment of diabetic retinopathy. J. Diabetes Complications 29, 99–104 (2015).

    PubMed  Google Scholar 

  29. 29.

    Silva, P. S. et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology 122, 949–956 (2015).

    PubMed  Google Scholar 

  30. 30.

    Talks, S. J., Manjunath, V., Steel, D. H., Peto, T. & Taylor, R. New vessels detected on wide-field imaging compared to two-field and seven-field imaging: implications for diabetic retinopathy screening image analysis. Br. J. Ophthalmol. 99, 1606–1609 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Aiello, L. P. et al. Comparison of early treatment diabetic retinopathy study standard 7-field imaging with ultrawide-field imaging for determining severity of diabetic retinopathy. JAMA Ophthalmol. 137, 65–73 (2019).

    PubMed  Google Scholar 

  32. 32.

    Wessel, M. M. et al. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina 32, 785–791 (2012).

    PubMed  Google Scholar 

  33. 33.

    Silva, P. S. et al. Diabetic retinopathy severity and peripheral lesions are associated with nonperfusion on ultrawide field angiography. Ophthalmology 122, 2465–2472 (2015).

    PubMed  Google Scholar 

  34. 34.

    Korot, E., Comer, G., Steffens, T. & Antonetti, D. A. Algorithm for the measure of vitreous hyperreflective foci in optical coherence tomographic scans of patients with diabetic macular edema. JAMA Ophthalmol. 134, 15–20 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Jia, Y. et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt. Express 20, 4710–4725 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Vujosevic, S. et al. Early microvascular and neural changes in patients with type 1 and type 2 diabetes mellitus without clinical signs of diabetic retinopathy. Retina 39, 435–445 (2019).

    PubMed  Google Scholar 

  37. 37.

    Spaide, R. F., Fujimoto, J. G., Waheed, N. K., Sadda, S. R. & Staurenghi, G. Optical coherence tomography angiography. Prog. Retin. Eye Res. 64, 1–55 (2018).

    PubMed  Google Scholar 

  38. 38.

    Haines, N. R., Manoharan, N., Olson, J. L., D’Alessandro, A. & Reisz, J. A. Metabolomics analysis of human vitreous in diabetic retinopathy and rhegmatogenous retinal detachment. J. Proteome Res. 17, 2421–2427 (2018).

    CAS  PubMed  Google Scholar 

  39. 39.

    Liew, G. et al. Metabolomics of diabetic retinopathy. Curr. Diab. Rep. 17, 102 (2017).

    PubMed  Google Scholar 

  40. 40.

    Moss, S. E., Klein, R. & Klein, B. E. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105, 998–1003 (1998).

    CAS  PubMed  Google Scholar 

  41. 41.

    Klein, R., Klein, B. E., Moss, S. E. & Cruickshanks, K. J. 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, 1801–1815 (1998).

    CAS  PubMed  Google Scholar 

  42. 42.

    Mishra, A. & Newman, E. A. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58, 1996–2004 (2010).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Nguyen, T. T. et al. Correlation of light-flicker-induced retinal vasodilation and retinal vascular caliber measurements in diabetes. Invest. Ophthalmol. Vis. Sci. 50, 5609–5613 (2009).

    PubMed  Google Scholar 

  44. 44.

    Pannicke, T. et al. Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes 55, 633–639 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Thompson, K. et al. Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Muller cells. PLoS ONE 13, e0193280 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    McDowell, R. E. et al. Muller glial dysfunction during diabetic retinopathy in rats is reduced by the acrolein-scavenging drug, 2-hydrazino-4,6-dimethylpyrimidine. Diabetologia 61, 2654–2667 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Portillo, J. C. et al. CD40 in retinal Muller cells induces P2X7-dependent cytokine expression in macrophages/microglia in diabetic mice and development of early experimental diabetic retinopathy. Diabetes 66, 483–493 (2017).

    CAS  PubMed  Google Scholar 

  48. 48.

    Karlstetter, M. et al. Retinal microglia: just bystander or target for therapy? Prog. Retin. Eye Res. 45, 30–57 (2015).

    PubMed  Google Scholar 

  49. 49.

    Mohamed, Q., Gillies, M. C. & Wong, T. Y. Management of diabetic retinopathy: a systematic review. JAMA 298, 902–916 (2007).

    CAS  PubMed  Google Scholar 

  50. 50.

    Simo, R., Sundstrom, J. M. & Antonetti, D. A. Ocular anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care 37, 893–899 (2014).

    CAS  PubMed  Google Scholar 

  51. 51.

    Titchenell, P. M. & Antonetti, D. A. Using the past to inform the future: anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy. Diabetes 62, 1808–1815 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Nguyen, Q. D. et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 119, 789–801 (2012).

    PubMed  Google Scholar 

  53. 53.

    Do, D. V. et al. One-year outcomes of the DA VINCI study of VEGF trap-eye in eyes with diabetic macular edema. Ophthalmology 119, 1658–1665 (2012).

    PubMed  Google Scholar 

  54. 54.

    Heier, J. S. et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology 123, 2376–2385 (2016).

    PubMed  Google Scholar 

  55. 55.

    Sun, J. K. et al. Rationale and application of the protocol S anti-vascular endothelial growth factor algorithm for proliferative diabetic retinopathy. Ophthalmology 126, 87–95 (2019).

    PubMed  Google Scholar 

  56. 56.

    Wells, J. A. et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 372, 1193–1203 (2015).

    CAS  PubMed  Google Scholar 

  57. 57.

    Arima, M. et al. Claudin-5 redistribution induced by inflammation leads to anti-VEGF-resistant diabetic macular edema. Diabetes 69, 981–999 (2020).

    CAS  PubMed  Google Scholar 

  58. 58.

    Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Miloudi, K. et al. NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy. Proc. Natl Acad. Sci. USA 116, 4538–4547 (2019).

    CAS  PubMed  Google Scholar 

  60. 60.

    Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Park, D. Y. et al. Plastic roles of pericytes in the blood-retinal barrier. Nat. Commun. 8, 15296 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Geraldes, P. et al. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15, 1298–1306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106, 1319–1331 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Xu, Q. et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 116, 883–895 (2004).

    CAS  PubMed  Google Scholar 

  66. 66.

    Ye, X. et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 139, 285–298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Wang, Y. et al. Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 151, 1332–1344 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Zhou, Y. et al. Canonical WNT signaling components in vascular development and barrier formation. J. Clin. Invest. 124, 3825–3846 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Tokunaga, C. C., Chen, Y. H., Dailey, W., Cheng, M. & Drenser, K. A. Retinal vascular rescue of oxygen-induced retinopathy in mice by norrin. Invest. Ophthalmol. Vis. Sci. 54, 222–229 (2013).

    CAS  PubMed  Google Scholar 

  70. 70.

    Ohlmann, A. et al. Norrin promotes vascular regrowth after oxygen-induced retinal vessel loss and suppresses retinopathy in mice. J. Neurosci. 30, 183–193 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Zeilbeck, L. F. et al. Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1. Exp. Eye Res. 145, 317–326 (2016).

    CAS  PubMed  Google Scholar 

  72. 72.

    Diaz-Coranguez, M., Lin, C. M., Liebner, S. & Antonetti, D. A. Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability. J. Biol. Chem. 295, 4647–4660 (2020).

    CAS  PubMed  Google Scholar 

  73. 73.

    Simo-Servat, O., Hernandez, C. & Simo, R. Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy. Mediators Inflamm. 2012, 872978 (2012).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Vujosevic, S. & Simo, R. Local and systemic inflammatory biomarkers of diabetic retinopathy: an integrative approach. Invest. Ophthalmol. Vis. Sci. 58, BIO68–BIO75 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Joussen, A. M. et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression. FASEB J. 16, 438–440 (2002).

    CAS  PubMed  Google Scholar 

  76. 76.

    Huang, H. et al. TNFα is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis. Invest. Ophthalmol. Vis. Sci. 52, 1336–1344 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Joussen, A. M. et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 18, 1450–1452 (2004).

    CAS  PubMed  Google Scholar 

  78. 78.

    Demircan, N., Safran, B. G., Soylu, M., Ozcan, A. A. & Sizmaz, S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye 20, 1366–1369 (2005).

    PubMed  Google Scholar 

  79. 79.

    Koleva-Georgieva, D. N., Sivkova, N. P. & Terzieva, D. Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy. Folia Med. 53, 44–50 (2011).

    Google Scholar 

  80. 80.

    Schoenberger, S. D. et al. Increased prostaglandin E2 (PGE2) levels in proliferative diabetic retinopathy and correlation with VEGF and inflammatory cytokines. Invest. Ophthalmol. Vis. Sci. 53, 5906–5911 (2012).

    CAS  PubMed  Google Scholar 

  81. 81.

    Yoshimura, T. et al. Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases. PLoS ONE 4, e8158 (2009).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Ogata, N. et al. Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment. Am. J. Ophthalmol. 132, 378–382 (2001).

    CAS  PubMed  Google Scholar 

  83. 83.

    Aveleira, C. A., Lin, C. M., Abcouwer, S. F., Ambrosio, A. F. & Antonetti, D. A. TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes 59, 2872–2882 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Titchenell, P. M. et al. Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction. Biochem. J. 446, 455–467 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Lin, C. M. et al. Inhibition of atypical protein kinase C reduces inflammation-induced retinal vascular permeability. Am. J. Pathol. 188, 2392–2405 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Gardner, T. W. & Sundstrom, J. M. A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Vis. Res. 139, 153–160 (2017).

    PubMed  Google Scholar 

  87. 87.

    Sun, J. K. et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-Year Medalist Study. Diabetes Care 34, 968–974 (2011).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Praidou, A. et al. Angiogenic growth factors and their inhibitors in diabetic retinopathy. Curr. Diabetes Rev. 6, 304–312 (2010).

    CAS  PubMed  Google Scholar 

  89. 89.

    Yokomizo, H. et al. Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy. Sci. Transl. Med. 11, eaau6627 (2019).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Garcia-Ramirez, M. et al. Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy. Diabetologia 52, 2633–2641 (2009).

    CAS  PubMed  Google Scholar 

  91. 91.

    Gao, B. B. et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat. Med. 13, 181–188 (2007).

    CAS  PubMed  Google Scholar 

  92. 92.

    Clermont, A. et al. Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats. Diabetes 60, 1590–1598 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Sodhi, A. et al. Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema. J. Clin. Invest. 129, 4593–4608 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Xin, X. et al. Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. Proc. Natl Acad. Sci. USA 110, E3425–E3434 (2013).

    CAS  PubMed  Google Scholar 

  95. 95.

    Bouleti, C. et al. Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke. Eur. Heart J. 34, 3657–3668 (2013).

    CAS  PubMed  Google Scholar 

  96. 96.

    Cho, D. I. et al. Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair. JCI Insight 4, e125437 (2019).

    PubMed Central  Google Scholar 

  97. 97.

    Cerani, A. et al. Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1. Cell Metab. 18, 505–518 (2013).

    CAS  PubMed  Google Scholar 

  98. 98.

    Wang, X. et al. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature 499, 306–311 (2013).

    CAS  PubMed  Google Scholar 

  99. 99.

    Kallenberg, D. et al. A humanized antibody against LRG1 that inhibits angiogenesis and reduces retinal vascular leakage. Preprint at bioRxiv https://doi.org/10.1101/2020.07.25.218149 (2020).

    Article  Google Scholar 

  100. 100.

    Duraisamy, A. J., Mishra, M., Kowluru, A. & Kowluru, R. A. Epigenetics and regulation of oxidative stress in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 59, 4831–4840 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Kowluru, R. A. Diabetic retinopathy, metabolic memory and epigenetic modifications. Vis. Res. 139, 30–38 (2017).

    PubMed  Google Scholar 

  102. 102.

    Barber, A. J. et al. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J. Clin. Invest. 102, 783–791 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Sohn, E. H. et al. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc. Natl Acad. Sci. USA 113, E2655–E2664 (2016).

    CAS  PubMed  Google Scholar 

  104. 104.

    Gardner, T. W., Abcouwer, S. F., Barber, A. J. & Jackson, G. R. An integrated approach to diabetic retinopathy research. Arch. Ophthalmol. 129, 230–235 (2011).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Lynch, S. K. & Abramoff, M. D. Diabetic retinopathy is a neurodegenerative disorder. Vis. Res. 139, 101–107 (2017).

    PubMed  Google Scholar 

  106. 106.

    Miller, W. P. et al. Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes. Diabetes 67, 110–119 (2018).

    CAS  PubMed  Google Scholar 

  107. 107.

    Bogdanov, P. et al. Topical administration of bosentan prevents retinal neurodegeneration in experimental diabetes. Int. J. Mol. Sci. 19, 3578 (2018).

    PubMed Central  Google Scholar 

  108. 108.

    Santos, A. R. et al. Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: cross-sectional analyses of baseline data of the EUROCONDOR project. Diabetes 66, 2503–2510 (2017).

    CAS  PubMed  Google Scholar 

  109. 109.

    Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C. & Scheltens, P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5, 64–74 (2006).

    PubMed  Google Scholar 

  110. 110.

    Kopf, D. & Frolich, L. Risk of incident Alzheimer’s disease in diabetic patients: a systematic review of prospective trials. J. Alzheimers Dis. 16, 677–685 (2009).

    PubMed  Google Scholar 

  111. 111.

    Cheung, C. Y., Ikram, M. K., Chen, C. & Wong, T. Y. Imaging retina to study dementia and stroke. Prog. Retin. Eye Res. 57, 89–107 (2017).

    PubMed  Google Scholar 

  112. 112.

    Sundstrom, J. M. et al. Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases. Invest. Ophthalmol. Vis. Sci. 59, 2264–2274 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Stitt, A. W. et al. The progress in understanding and treatment of diabetic retinopathy. Prog. Retin. Eye Res. 51, 156–186 (2016).

    PubMed  Google Scholar 

  114. 114.

    Wei, Y. et al. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Proc. Natl Acad. Sci. USA 112, E6927–E6936 (2015).

    CAS  PubMed  Google Scholar 

  115. 115.

    Xu, Z. et al. NRF2 plays a protective role in diabetic retinopathy in mice. Diabetologia 57, 204–213 (2014).

    CAS  PubMed  Google Scholar 

  116. 116.

    Xu, Z. et al. Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion. J. Neurochem. 133, 233–241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Abcouwer, S. F. et al. Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 51, 5920–5933 (2010).

    PubMed  Google Scholar 

  118. 118.

    Muthusamy, A. et al. Ischemia-reperfusion injury induces occludin phosphorylation/ubiquitination and retinal vascular permeability in a VEGFR-2-dependent manner. J. Cereb. Blood Flow. Metab. 34, 522–531 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Hui, Q. et al. Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury. Free Radic. Biol. Med. 146, 181–188 (2020).

    CAS  PubMed  Google Scholar 

  120. 120.

    Stitt, A. W. et al. Vascular stem cells and ischaemic retinopathies. Prog. Retin. Eye Res. 30, 149–166 (2011).

    CAS  PubMed  Google Scholar 

  121. 121.

    Mohan, R. & Kohner, E. M. Retinal revascularisation in diabetic retinopathy. Br. J. Ophthalmol. 70, 114–117 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Takahashi, K., Kishi, S., Muraoka, K. & Shimizu, K. Reperfusion of occluded capillary beds in diabetic retinopathy. Am. J. Ophthalmol. 126, 791–797 (1998).

    CAS  PubMed  Google Scholar 

  123. 123.

    Abaci, A. et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99, 2239–2242 (1999).

    CAS  PubMed  Google Scholar 

  124. 124.

    Hernandez, S. L. et al. Characterization of circulating and endothelial progenitor cells in patients with extreme-duration type 1 diabetes. Diabetes Care 37, 2193–2201 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Altabas, V. Diabetes, endothelial dysfunction, and vascular repair: what should a diabetologist keep his eye on? Int. J. Endocrinol. 2015, 848272 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Patel, J. et al. Functional definition of progenitors versus mature endothelial cells reveals key SoxF-dependent differentiation process. Circulation 135, 786–805 (2017).

    CAS  PubMed  Google Scholar 

  127. 127.

    Naito, H. et al. Endothelial side population cells contribute to tumor angiogenesis and antiangiogenic drug resistance. Cancer Res. 76, 3200–3210 (2016).

    CAS  PubMed  Google Scholar 

  128. 128.

    Iba, T. et al. Isolation of tissue-resident endothelial stem cells and their use in regenerative medicine. Inflamm. Regen. 39, 9 (2019).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Ingram, D. A. et al. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105, 2783–2786 (2005).

    CAS  PubMed  Google Scholar 

  130. 130.

    Kovacic, J. C. & Boehm, M. Resident vascular progenitor cells: an emerging role for non-terminally differentiated vessel-resident cells in vascular biology. Stem Cell Res. 2, 2–15 (2009).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Naito, H., Kidoya, H., Sakimoto, S., Wakabayashi, T. & Takakura, N. Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J. 31, 842–855 (2012).

    CAS  PubMed  Google Scholar 

  132. 132.

    Wakabayashi, T. et al. CD157 marks tissue-resident endothelial stem cells with homeostatic and regenerative properties. Cell Stem Cell 22, 384–397 (2018).

    CAS  PubMed  Google Scholar 

  133. 133.

    Sekiguchi, H., Ii, M. & Losordo, D. W. The relative potency and safety of endothelial progenitor cells and unselected mononuclear cells for recovery from myocardial infarction and ischemia. J. Cell Physiol. 219, 235–242 (2009).

    CAS  PubMed  Google Scholar 

  134. 134.

    Grant, M. B. et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat. Med. 8, 607–612 (2002).

    CAS  PubMed  Google Scholar 

  135. 135.

    Otani, A. et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J. Clin. Invest. 114, 765–774 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Otani, A. et al. Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis. Nat. Med. 8, 1004–1010 (2002).

    CAS  PubMed  Google Scholar 

  137. 137.

    O’Neill, C. L. et al. Endothelial cell-derived pentraxin 3 limits the vasoreparative therapeutic potential of circulating angiogenic cells. Cardiovasc. Res. 112, 677–688 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Medina, R. J. et al. Endothelial progenitors: a consensus statement on nomenclature. Stem Cell Transl. Med. 6, 1316–1320 (2017).

    Google Scholar 

  139. 139.

    O’Neill, C. L. et al. Therapeutic revascularisation of ischaemic tissue: the opportunities and challenges for therapy using vascular stem/progenitor cells. Stem Cell Res. Ther. 3, 31 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Park, S. S. et al. Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings. Invest. Ophthalmol. Vis. Sci. 56, 81–89 (2015).

    CAS  PubMed Central  Google Scholar 

  141. 141.

    Chambers, S. E. J. et al. The vasoreparative function of myeloid angiogenic cells is impaired in diabetes through the induction of IL1β. Stem Cells 36, 834–843 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Medina, M. J. et al. Outgrowth endothelial cells characterisation and their potential for reversing ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 51, 5906–5913 (2010).

    PubMed  Google Scholar 

  143. 143.

    Medina, R. J. et al. Ex-vivo expansion of human endothelial progenitors leads to IL-8-mediated replicative senescence and impaired vasoreparative function. Stem Cells 31, 1657–1668 (2013).

    CAS  PubMed  Google Scholar 

  144. 144.

    Yoder, M. C. Defining human endothelial progenitor cells. J. Thromb. Haemost. 7, 49–52 (2009).

    CAS  PubMed  Google Scholar 

  145. 145.

    Heo, S. C. et al. WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells. Stem Cells 32, 779–790 (2014).

    CAS  PubMed  Google Scholar 

  146. 146.

    Bertelli, P. M. et al. Vascular regeneration for ischemic retinopathies: hope from cell therapies. Curr. Eye Res. 45, 372–384 (2020).

    PubMed  Google Scholar 

  147. 147.

    Prasain, N. et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat. Biotechnol. 32, 1151–1157 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Reid, E. et al. Preclinical evaluation and optimization of a cell therapy using human cord blood-derived endothelial colony-forming cells for ischemic retinopathies. Stem Cell Transl. Med. 7, 59–67 (2018).

    CAS  Google Scholar 

  149. 149.

    Sakimoto, S. et al. CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect. JCI Insight 2, e89906 (2017).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Cahoon, J. M. et al. Intravitreal AAV2.COMP-Ang1 prevents neurovascular degeneration in a murine model of diabetic retinopathy. Diabetes 64, 4247–4259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Mendel, T. A. et al. Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy. PLoS ONE 8, e65691 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Hajmousa, G. et al. Human adipose tissue-derived stromal cells act as functional pericytes in mice and suppress high-glucose-induced proinflammatory activation of bovine retinal endothelial cells. Diabetologia 61, 2371–2385 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Langhe, R. & Pearson, R. A. Rebuilding the retina: prospects for Muller glial-mediated self-repair. Curr. Eye Res. 45, 349–360 (2020).

    PubMed  Google Scholar 

  154. 154.

    Ahmad, I., Teotia, P., Erickson, H. & Xia, X. Recapitulating developmental mechanisms for retinal regeneration. Prog. Retin. Eye Res. 76, 100824 (2019).

    PubMed  Google Scholar 

  155. 155.

    Zerti, D., Collin, J., Queen, R., Cockell, S. J. & Lako, M. Understanding the complexity of retina and pluripotent stem cell derived retinal organoids with single cell RNA sequencing: current progress, remaining challenges and future prospective. Curr. Eye Res. 45, 385–396 (2020).

    CAS  PubMed  Google Scholar 

  156. 156.

    Galloway, C. A. et al. Drusen in patient-derived hiPSC-RPE models of macular dystrophies. Proc. Natl Acad. Sci. USA 114, E8214–E8223 (2017).

    CAS  PubMed  Google Scholar 

  157. 157.

    Kiamehr, M. et al. Compromised barrier function in human induced pluripotent stem-cell-derived retinal pigment epithelial cells from type 2 diabetic patients. Int. J. Mol. Sci. 20, 3773 (2019).

    CAS  PubMed Central  Google Scholar 

  158. 158.

    Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to David A. Antonetti.

Ethics declarations

Competing interests

D.A.A. has received grant support from F. Hoffmann-La Roche, Inc. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks R. Simó and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

UKRI: https://gtr.ukri.org/projects?ref=MR%2FN006410%2F1

Glossary

Vitreous

The clear gel filling the space between the retina and the lens.

Choroid

The vascular bed adjacent to the retinal pigmented epithelium (RPE) supporting the rods and cones of the outer retina that are on the opposing side of the RPE.

Posterior pole

The posterior segment of the human retina visible during ophthalmoscopy made up of the optic disc (optic nerve head) and macula, or avascular central area including the fovea, or thinned retina with high cone density responsible for high visual acuity.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Antonetti, D.A., Silva, P.S. & Stitt, A.W. Current understanding of the molecular and cellular pathology of diabetic retinopathy. Nat Rev Endocrinol 17, 195–206 (2021). https://doi.org/10.1038/s41574-020-00451-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing