Congdon, N. G., Friedman, D. S. & Lietman, T. Important causes of visual impairment in the world today. Journal of the American Medical Association 290(15), 2057–2060 (2003).
Tang, J. & Kern, T. S. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 30(5), 343–58 (2011).
Barber, A. J. et al. Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin. Journal of Clinical Investigation 102(4), 783–791 (1998).
Antonetti, D. A. et al. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55(9), 2401–2411 (2006).
Simo, R., Carrasco, E., Garcıa-Ramırez, M. & Hernandez, C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Current Diabetes Reviews 2(1), 71–98 (2006).
Klein, R. et al. The Wisconsin epidemiologic study of diabetic retinopathy II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 102, 520–526 (1984).
Klein, R. et al. The Wisconsin epidemiologic study of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 102, 527–532 (1984).
Madsen-Bouterse, S. A. & Kowluru, R. A. Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Reviews in Endocrine and Metabolic Disorders 9(4), 315–327 (2008).
Halliwell, B. & Gutteridge, J. M. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J. 219, 1–14 (1984).
Hare, D. J. Is early-life iron exposure critical in neurodegeneration? Nat Rev Neurol. 11(9), 536–44 (2015).
Schröder, N., Figueiredo, L. S. & de Lima, M. N. Role of brain iron accumulation in cognitive dysfunction: evidence from animal models and human studies. J Alzheimers Dis. 34(4), 797–81 (2013).
Greenough, M. A., Ramírez Munoz, A., Bush, A. I. & Opazo, C. M. Metallo-pathways to Alzheimer’s disease: lessons from genetic disorders of copper trafficking. Metallomics 8(9), 831–9 (2016).
Wong, R. W., Richa, D. C., Hahn, P., Green, W. R. & Dunaief, J. L. Iron toxicity as a potential factor in AMD. Retina 27(8), 997–1003 (2007).
Song, D. et al. AMD-like retinopathy associated with intravenous iron. Exp Eye Res. 151, 122–33 (2016).
Dawczynski, J., Blum, M., Winnefeld, K. & Strobel, J. Increased content of zinc and iron in human cataractous lenses. Biological Trace Element Research 90(1), 15–24 (2002).
Farkas, R. H. et al. Increased expression of iron-regulating genes in monkey and human glaucoma. Investigative Ophthalmology and Visual Science 45(5), 1410–1417 (2004).
Konerirajapuram, N. S. et al. Trace elements iron, copper and zinc in vitreous of patients with various vitreoretinal diseases. Indian J Ophthalmol. 52(2), 145–8 (2004).
Weller, M., Clausen, R., Heimann, K. & Wiedemann, P. Iron-binding proteins in the human vitreous: lactoferrin and transferrin in health and in proliferative intraocular disorders. Ophthalmic Res. 22(3), 194–200 (1990).
Galton, D. J. Diabetic retinopathy and hemochromatosis. Br Med J. 1(5443), 1169 (1965).
Walsh, C. H. & Malins, J. M. Proliferative retinopathy in a patient with diabetes mellitus and idiopathic haemochromatosis. Br Med J. 2(6129), 16–7 (1978).
Peterlin, B., Globocnik Petrovic, M., Makuc, J., Hawlina, M. & Petrovic, D. A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes. J Hum Genet 48(12), 646–9 (2003).
Ciudin, A., Hernández, C. & Simó, R. Iron overload in diabetic retinopathy: a cause or a consequence of impaired mechanisms? Exp Diabetes Res. pii: 714108 (2010).
Kobori, H., Nangaku, M., Navar, L. G. & Nishiyama, A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 59, 251–287 (2007).
Wagner, J. et al. Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol. 80(2), 159–63 (1996).
Nagai, N. et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci. 48(9), 4342–50 (2007).
Chaturvedi, N. et al. Direct Programme Study Group. Effect of candesartan on prevention (Direct-Prevent 1) and progression (DIRECT-Project 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372(9647), 1394–402 (2008).
Sjolie, A. K. et al. Direct Programme Study Group Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (Direct-Protect 2): a randomised placebo-controlled trial. Lancet 372, 1385–1393 (2008).
Mauer, M. et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 361(1), 40–51 (2009).
He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004).
Hebert, S. C. Physiology: orphan detectors of metabolism. Nature 429, 143–145 (2004).
Toma, I. et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest. 118(7), 2526–34 (2008).
Vargas, S. L., Toma, I., Kang, J. J., Meer, E. J. & Peti-Peterdi, J. Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J Am Soc Nephrol. 20(5), 1002–11 (2009).
Sapieha, P. et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med. 14, 1067–1076 (2008).
Gnana-Prakasam, J. P. et al. Expression and Iron-Dependent Regulation of Succinate Receptor GPR91 in Retinal Pigment Epithelium. Invest Ophthalmol Vis Sci. 52(6), 3751–8 (2011).
Arjunan, P. et al. Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis. Invest Ophthalmol Vis Sci. 57(4), 1612–9 (2016).
Gnana-Prakasam, J. P. et al. Absence of Iron-regulatory Protein HFE Results in Hyper-proliferation of Retinal Pigment Epithelium Mediated by Induction of Cystine/Glutamate Transporter. Biochem J. 424(2), 243–252 (2009).
Gnana-Prakasam, J. P. et al. Loss of HFE Leads to Progression of Tumor Phenotype in Primary Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 54(1), 63–71 (2013).
Cunha-Vaz, J., Bernardes, R. & Lobo, C. Blood-retinal barrier. Eur J Ophthalmol. 21(Suppl 6), S3–9 (2011).
Vikram, A., Tripathi, D. N., Kumar, A. & Singh, S. Oxidative stress and inflammation in diabetic complications. Int J Endocrinol. 679754 (2014).
Baynes, J. W. & Thorpe, S. R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48(1), 1–9 (1999).
Kowluru, R. A. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52(3), 818–823 (2003).
Gnana-Prakasam, J. P. et al. Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/toll-like receptor-4 pathway independent of Hfe. Biochem J. 411(1), 79–88 (2008).
Nakamura, K. et al. Activation of the NLRP3 inflammasome by cellular labile iron. Exp Hematol. 44(2), 116–24 (2016).
Gelfand, B. D. et al. Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome. Cell Rep. 11, 1686–1693 (2015).
Loukovaara, S. et al. NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol. Epub ahead of print (2017).
Wang, B. et al. Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 3(4), 263–74 (2015).
Jiang, R. et al. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. J Am Med Assoc. 291(6), 711–717 (2004).
Bao, W., Rong, Y., Rong, S. & Liu, L. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and metaanalysis. BMC Med. 10(1), 119 (2012).
Ford, E. S. & Cogswell, M. E. Diabetes and serum ferritin concentration among US adults. Diabetes Care 22(12), 1978–1983 (1999).
Eshed, I., Elis, A. & Lishner, M. Plasma ferritin and type 2 diabetes mellitus: a critical review. Endocr Res 27(1–2), 91–97 (2001).
Arredondo, M. et al. Cross-talk between body iron stores and diabetes: iron stores are associated with activity and microsatellite polymorphism of the heme oxygenase and type 2 diabetes. Biol Trace Elem Res. 143(2), 625–636 (2011).
Wolff, S. P. Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the etiology of diabetes mellitus and complications. Br Med Bull 49(3), 642–652 (1993).
Swaminathan, S., Fonseca, V. A., Alam, M. G. & Shah, S. V. The role of iron in diabetes and its complications. Diabetes Care 30(7), 1926–1933 (2007).
Li, X. et al. Iron increases liver injury through oxidative/nitrative stress in diabetic rats: involvement of nitrotyrosination of glucokinase. Biochimie 94(12), 2620–2627 (2012).
Fung, T. T. et al. Dietary patterns, meat intake, and the risk of type 2 diabetes in women. Arch Intern Med. 164(20), 2235–2240 (2004). 23.
Li, H. et al. Body iron stores and dietary iron intake in relation to diabetes in adults in North China. Diabetes Care 31(2), 285–286 (2008).
Dominguez, J. H., Liu, Y. & Kelly, K. J. Renal iron overload in rats with diabetic nephropathy. Physiol Rep 3(12), e12654 (2015).
Ward, D. T. et al. Altered expression of iron transport proteins in streptozotocin-induced diabetic rat kidney. Biochim Biophys Acta. 1740, 79–84 (2005).
Howard, R. L., Buddington, B. & Alfrey, A. C. Urinary albumin, transferrin and iron excretion in diabetic patients. Kidney Intl. 40, 923–926 (1991).
Remuzzi, A., Puntorieri, S., Brugnetti, B., Bertani, T. & Remuzzi, G. Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics. Kidney Int. 39, 647–652 (1991).
Nath, K. A., Fischereder, M. & Hostetter, T. H. The role of oxidants in progressive renal injury. Kidney Int. 45, S111–S115 (1994).
Cussimanio, B. L., Booth, A. A., Todd, P., Hudson, B. G. & Khalifah, R. G. Unusual susceptibility of heme proteins to damage by glucose during non-enzymatic glycation. Biophysical Chemistry 105(2-3), 743–755 (2003).
Wessling-Resnick, M. Iron Homeostasis and the Inflammatory Response. Annu Rev Nutr. 30, 105–122 (2010).
Villarroel, M., Ciudin, A., Hernández, C. & Simó, R. Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes 1(2), 57–64 (2010).
Silva, K. C., Rosales, M. A., Biswas, S. K., Lopes de Faria, J. B. & Lopes de Faria, J. M. Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes. Diabetes 58(6), 1382–90 (2009).
Kurihara, T. et al. Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina. Diabetes 57(8), 2191–8 (2008).
Ozawa, Y., Yuki, K., Yamagishi, R., Tsubota, K. & Aihara, M. Renin-angiotensin system involvement in the oxidative stress-induced neurodegeneration of cultured retinal ganglion cells. Jpn J Ophthalmol. 57(1), 126–32 (2013).
Kawamura, H. et al. Effects of angiotensin II on the pericyte containing microvasculature of the rat retina. J Physiol. 561(Pt 3), 671–83 (2004).
Otani, A., Takagi, H., Suzuma, K. & Honda, Y. Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res. 82(5), 619–28 (1998).
Otani, A. et al. Angiotensin II-stimulated vascular endothelial growth factor expression in bovine retinal pericytes. Invest Ophthalmol Vis Sci. 41(5), 1192–9 (2000).
Hu, J., Wu, Q., Li, T., Chen, Y. & Wang, S. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91. Exp Eye Res. 109, 31–9 (2013).
Gambhir, D. et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 53, 2208–2217 (2012).
Mukaide, T. et al. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. Free Radic Res. 48(9), 990–5 (2014).
Wang, Y. et al. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. Cancer Sci. 107(3), 250–257 (2016).
Gnana-Prakasam, J. P. et al. Iron-mediated Retinal Degeneration in Hemojuvelin Knockout Mice. Biochem J. 441(2), 599–608 (2012).
Gnana-Prakasam, J. P., Zhang, M., Atherton, S. S., Smith, S. B. & Ganapathy, V. Expression of Iron Regulatory Protein Hemojuvelin in Retina and its Potential Role in Cytomegalovirus induced Retinitis. Biochem J. 419(3), 533–543 (2009).
Longbottom, R. et al. Genetic ablation of retinal pigment epithelial cells reveals the adaptive response of the epithelium and impact on photoreceptors. Proc Natl Acad Sci USA 106, 18728–18733 (2009).
Tawfik, A., Gnana-Prakasam, J. P., Smith, S. B. & Ganapathy, V. Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis. Invest Ophthalmol Vis Sci. 55(6), 3616–25 (2014).