Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

eLife

Volumn 5, Issue MARCH2016, 2016, Pages

  Kurihara, Toshihide ^a,d   Westenskow, Peter D ^a,b   Gantner, Marin L ^b   Usui, Yoshihiko ^a,e   Schultz, Andrew ^a   Bravo, Stephen ^a   Aguilar, Edith ^a   Wittgrove, Carli ^a   Friedlander, Mollie S H ^a   Paris, Liliana P ^a   Chew, Emily ^c   Siuzdak, Gary ^a   Friedlander, Martin ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b Division of Basic Science   (United States)

^c NATIONAL EYE INSTITUTE   (United States)

^d KEIO UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^e TOKYO MEDICAL UNIVERSITY HOSPITAL   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

AGE RELATED MACULAR DEGENERATION; ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOROID CAPILLARY LAYER; CONTROLLED STUDY; ELECTRON MICROSCOPY; ELECTRORETINOGRAPHY; GLUCOSE METABOLISM; HYPOXIA; IMMUNOHISTOCHEMISTRY; LIPID METABOLISM; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; METABOLIC STRESS; MOUSE; NONHUMAN; PIGMENT EPITHELIUM; STARVATION; ANIMAL; DISEASE MODEL; EPITHELIUM CELL; MACULAR DEGENERATION; PATHOPHYSIOLOGY; PHOTORECEPTOR CELL; PHYSIOLOGICAL STRESS; PHYSIOLOGY; RETINAL PIGMENT EPITHELIUM;

ANIMALS; DISEASE MODELS, ANIMAL; EPITHELIAL CELLS; HYPOXIA; MACULAR DEGENERATION; MICE; PHOTORECEPTOR CELLS; RETINAL PIGMENT EPITHELIUM; STRESS, PHYSIOLOGICAL;

EID: 84969248532     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.14319     Document Type: Article

References (101)

1. Baba T, Bhutto IA, Merges C, Grebe R, Emmert D, McLeod DS, Armstrong D, Lutty GA. 2010. A rat model for choroidal neovascularization using subretinal lipid hydroperoxide injection. The American Journal of Pathology 176:3085–3097. doi: 10.2353/ajpath.2010.090989
2. Bazan HE, Bazan NG, Feeney-Burns L, Berman ER. 1990. Lipids in human lipofuscin-enriched subcellular fractions of two age populations. Comparison with rod outer segments and neural retina. Investigative Ophthalmology & Visual Science 31:1433–1443.
3. Bhutto I, Lutty G. 2012. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Molecular Aspects of Medicine 33:295–317. doi: 10.1016/j.mam.2012.04.005
4. Bird AC. 2010. Therapeutic targets in age-related macular disease. The Journal of Clinical Investigation 120: 3033–3041. doi: 10.1172/JCI42437
5. Bird AC, Phillips RL, Hageman GS. 2014. Geographic atrophy: a histopathological assessment. JAMA Ophthalmology 132:338–345. doi: 10.1001/jamaophthalmol.2013.5799
6. Blasiak J, Petrovski G, Veréb Z, Facskó A, Kaarniranta K. 2014. Oxidative stress, hypoxia, and autophagy in the neovascular processes of age-related macular degeneration. BioMed Research International 2014. doi: 10.1155/2014/768026
7. Boltz A, Luksch A, Wimpissinger B, Maar N, Weigert G, Frantal S, Brannath W, Garhöfer G, Ergun E, Stur M, Schmetterer L. 2010. Choroidal blood flow and progression of age-related macular degeneration in the fellow eye in patients with unilateral choroidal neovascularization. Investigative Ophthalmology & Visual Science 51: 4220–4225. doi: 10.1167/iovs.09-4968
8. Bressler SB, Maguire MG, Bressler NM, Fine SL. 1990. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. the Macular Photocoagulation Study Group. Archives of Ophthalmology 108:1442–1447. doi: 10.1001/archopht.1990.01070120090035
9. Cao S, Walker GB, Wang X, Cui JZ, Matsubara JA. 2013. Altered cytokine profiles of human retinal pigment epithelium: oxidant injury and replicative senescence. Molecular Vision 19:718–728.
10. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, Tosakulwong N, Pericak-Vance MA, Campochiaro PA, Klein ML, Tan PL, Conley YP, Kanda A, Kopplin L, Li Y, Augustaitis KJ, Karoukis AJ, Scott WK, Agarwal A, Kovach JL, et al. 2010. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 107:7401–7406. doi: 10.1073/pnas.0912702107
11. Chertov AO, Holzhausen L, Kuok IT, Couron D, Parker E, Linton JD, Sadilek M, Sweet IR, Hurley JB. 2011. Roles of glucose in photoreceptor survival. The Journal of Biological Chemistry 286:34700–34711. doi: 10.1074/jbc.M111.279752
12. Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Davis MD, Ferris FL.Age-Related Eye Disease Study Research Group. 2014. Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmology 132:272–277. doi: 10.1001/jamaophthalmol.2013.6636
13. Chiu CJ, Milton RC, Gensler G, Taylor A. 2007. Association between dietary glycemic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study. The American Journal of Clinical Nutrition 86:180–188.
14. Chiu CJ, Taylor A. 2011. Dietary hyperglycemia, glycemic index and metabolic retinal diseases. Progress in Retinal and Eye Research 30:18–53. doi: 10.1016/j.preteyeres.2010.09.001
15. Coscas F, Puche N, Coscas G, Srour M, Français C, Glacet-Bernard A, Querques G, Souied EH. 2014. Comparison of macular choroidal thickness in adult onset foveomacular vitelliform dystrophy and age-related macular degeneration. Investigative Ophthalmology & Visual Science 55:64–69. doi: 10.1167/iovs.13-12931
16. Curcio CA, Millican CL. 1999. Basal linear deposit and large drusen are specific for early age-related maculopathy. Archives of Ophthalmology 117:329–339. doi: 10.1001/archopht.117.3.329
17. Feeney-Burns L, Hilderbrand ES, Eldridge S. 1984. Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Investigative Ophthalmology & Visual Science 25:195–200.
18. Finnemann SC, Leung LW, Rodriguez-Boulan E. 2002. The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proceedings of the National Academy of Sciences of the United States of America 99:3842–3847. doi: 10.1073/pnas.052025899
19. Foulds WS. 1990. Retinal metabolism and the choroidal circulation. Eye 4 (Pt 2):ix. doi: 10.1038/eye.1990.34
20. Friedman DS, O’Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J. Eye Diseases Prevalence Research Group. 2004. Prevalence of age-related macular degeneration in the United States. Archives of Ophthalmology 122:564–572. doi: 10.1001/archopht.122.4.564
21. Gass JD. 1973. Drusen and disciform macular detachment and degeneration. Archives of Ophthalmology 90: 206–217. doi: 10.1001/archopht.1973.01000050208006
22. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N. 1999. VEGF is required for growth and survival in neonatal mice. Development 126:1149–1159.
23. Glunde K, Shah T, Winnard PT, Raman V, Takagi T, Vesuna F, Artemov D, Bhujwalla ZM. 2008. Hypoxia regulates choline kinase expression through hypoxia-inducible factor-1 alpha signaling in a human prostate cancer model. Cancer Research 68:172–180. doi: 10.1158/0008-5472.CAN-07-2678
24. Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, Slocum KL, Pu M, Lin F, Vickers C, Joud-Caldwell C, Chung F, Yin H, Handly ED, Straub C, Growney JD, Vander Heiden MG, Murphy AN, Pagliarini R, Metallo CM. 2014. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Research 74:3317–3331. doi: 10.1158/0008-5472.CAN-14-0772-T
25. Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. 2007. Acute postnatal ablation of Hif-2alpha results in anemia. Proceedings of the National Academy of Sciences of the United States of America 104:2301–2306. doi: 10.1073/pnas.0608382104
26. Haase VH, Glickman JN, Socolovsky M, Jaenisch R. 2001. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 98:1583–1588. doi: 10.1073/pnas.98.4.1583
27. Hogan MJ. 1972. Role of the retinal pigment epithelium in macular disease. Transactions-American Academy of Ophthalmology and Otolaryngology. American Academy of Ophthalmology and Otolaryngology 76:64–80.
28. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. 1994. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Archives of Ophthalmology 112:402–406. doi: 10.1001/archopht.1994.01090150132035
29. Holz FG, Bellmann C, Margaritidis M, Schütt F, Otto TP, Völcker HE. 1999. Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration. Graefe’s Archive for Clinical and Experimental Ophthalmology 237: 145–152. doi: 10.1007/s004170050209
30. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. 2002. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology 22:7004–7014. doi: 10.1128/mcb.22.20.7004-7014.2002
31. Imanishi Y, Gerke V, Palczewski K, Retinosomes PK. 2004. Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. The Journal of Cell Biology 166:447–453. doi: 10.1083/jcb.200405110
32. Jager RD, Mieler WF, Miller JW. 2008. Age-related macular degeneration. The New England Journal of Medicine 358:2606–2617. doi: 10.1056/NEJMra0801537
33. Jonas JB, Forster TM, Steinmetz P, Schlichtenbrede FC, Harder BC. 2014. Choroidal thickness in age-related macular degeneration. Retina 34:1149–1155. doi: 10.1097/IAE.0000000000000035
34. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT. 1998. Genetic association of apolipoprotein E with age-related macular degeneration. American Journal of Human Genetics 63:200–206. doi: 10.1086/301901
35. Krohne TU, Westenskow PD, Kurihara T, Friedlander DF, Lehmann M, Dorsey AL, Li W, Zhu S, Schultz A, Wang J, Siuzdak G, Ding S, Friedlander M. 2012. Generation of retinal pigment epithelial cells from small molecules and OCT4 reprogrammed human induced pluripotent stem cells. Stem Cells Translational Medicine 1:96–109. doi: 10.5966/sctm.2011-0057
36. Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M. 2012. Targeted deletion of Vegfa in adult mice induces vision loss. The Journal of Clinical Investigation 122:4213–4217. doi: 10.1172/JCI65157
37. Lakkaraju A, Finnemann SC, Rodriguez-Boulan E. 2007. The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 104:11026–11031. doi: 10.1073/pnas.0702504104
38. Le YZ, Zheng W, Rao PC, Zheng L, Anderson RE, Esumi N, Zack DJ, Zhu M. 2008. Inducible expression of cre recombinase in the retinal pigmented epithelium. Investigative Ophthalmology & Visual Science 49:1248–1253. doi: 10.1167/iovs.07-1105
39. Le YZ, Bai Y, Zhu M, Zheng L. 2010. Temporal requirement of RPE-derived VEGF in the development of choroidal vasculature. Journal of Neurochemistry 112:1584–1592. doi: 10.1111/j.1471-4159.2010.06573.x
40. Lee JY, Lee DH, Lee JY, Yoon YH. 2013. Correlation between subfoveal choroidal thickness and the severity or progression of nonexudative age-related macular degeneration. Investigative Ophthalmology & Visual Science 54:7812–7818. doi: 10.1167/iovs.13-12284
41. Linton JD, Holzhausen LC, Babai N, Song H, Miyagishima KJ, Stearns GW, Lindsay K, Wei J, Chertov AO, Peters TA, Caffe R, Song H, Seeliger MW, Tanimoto N, Song H, Bolton L, Kuok DL, Sweet IR, Bartoletti TM, Radu RA, et al. 2010. Flow of energy in the outer retina in darkness and in light. Proceedings of the National Academy of Sciences of the United States of America 107:8599–8604. doi: 10.1073/pnas.1002471107
42. Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL. 2011. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:732–744. doi: 10.1016/j.cell.2011.03.054
43. Marc RE, Jones BW, Watt CB, Strettoi E. 2003. Neural remodeling in retinal degeneration. Progress in Retinal and Eye Research 22:607–655. doi: 10.1016/s1350-9462(03)00039-9
44. Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR. 2005. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. The American Journal of Pathology 167:1451–1459. doi: 10.1016/S0002-9440(10)61231-X
45. McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA. 2009. Relationship between RPE and choriocapillaris in age-related macular degeneration. Investigative Ophthalmology & Visual Science 50:4982–4991. doi: 10.1167/iovs.09-3639
46. Metelo AM, Noonan HR, Li X, Jin Y, Baker R, Kamentsky L, Zhang Y, van Rooijen E, Shin J, Carpenter AE, Yeh JR, Peterson RT, Iliopoulos O. 2015. Pharmacological Hif2a inhibition improves VHL disease-associated phenotypes in zebrafish model. The Journal of Clinical Investigation 125:1987–1997. doi: 10.1172/JCI73665
47. Moore DJ, Hussain AA, Marshall J. 1995. Age-related variation in the hydraulic conductivity of Bruch’s membrane. Investigative Ophthalmology & Visual Science 36:1290–1297.
48. Morgado PB, Chen HC, Patel V, Herbert L, Kohner EM. 1994. The acute effect of smoking on retinal blood flow in subjects with and without diabetes. Ophthalmology 101:1220–1226. doi: 10.1016/s0161-6420(94)31185-7
49. Mullins RF, Johnson MN, Faidley EA, Skeie JM, Huang J. 2011. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Investigative Ophthalmology & Visual Science 52:1606–1612. doi: 10.1167/iovs.10-6476
50. Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. 2007. A global double-fluorescent Cre reporter mouse. Genesis 45:593–605. doi: 10.1002/dvg.20335
51. Nayak BK, Feliers D, Sudarshan S, Friedrichs WE, Day RT, New DD, Fitzgerald JP, Eid A, Denapoli T, Parekh DJ. 2012. Stabilization of HIF-2alpha through redox regulation of mTORC2 activation and initiation of mRNA translation. Oncogene 2012:333. doi: 10.1038/onc.2012.333
52. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, Tan PL, Oh EC, Merriam JE, Souied E, Bernstein PS, Li B, Frederick JM, Zhang K, Brantley MA, Lee AY, Zack DJ, Campochiaro B, Campochiaro P, Ripke S, et al. 2010. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proceedings of the National Academy of Sciences of the United States of America 107:7395–7400. doi: 10.1073/pnas.0912019107
53. Pauleikhoff D, Harper CA, Marshall J, Bird AC. 1990. Aging changes in Bruch’s membrane. a histochemical and morphologic study. Ophthalmology 97:171–178. doi: 10.1016/s0161-6420(90)32619-2
54. Pauleikhoff D, Zuels S, Sheraidah GS, Marshall J, Wessing A, Bird AC. 1992. Correlation between biochemical composition and fluorescein binding of deposits in Bruch’s membrane. Ophthalmology 99:1548–1553. doi: 10.1016/s0161-6420(92)31768-3
55. Punzo C, Kornacker K, Cepko CL. 2009. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nature Neuroscience 12:44–52. doi: 10.1038/nn.2234
56. Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, Bobrovnikova-Marjon E, Diehl JA, Keith B, Simon MC. 2015. HIF2a-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discovery 5:652–667. doi: 10.1158/2159-8290.CD-14-1507
57. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT. 1994. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Investigative Ophthalmology & Visual Science 35:2857–2864.
58. Remsch H, Spraul CW, Lang GK, Lang GE. 2000. Changes of retinal capillary blood flow in age-related maculopathy. Graefe’s Archive for Clinical and Experimental Ophthalmology 238:960–964. doi: 10.1007/s004170000202
59. Rinaldo P, Cowan TM, Matern D. 2008. Acylcarnitine profile analysis. Genetics in Medicine 10:151–156. doi: 10.1097/GIM.0b013e3181614289
60. Rini BI, Atkins MB. 2009. Resistance to targeted therapy in renal-cell carcinoma. The Lancet. Oncology 10:992–1000. doi: 10.1016/S1470-2045(09)70240-2
61. Rogers JL, Bayeh L, Scheuermann TH, Longgood J, Key J, Naidoo J, Melito L, Shokri C, Frantz DE, Bruick RK, Gardner KH, MacMillan JB, Tambar UK. 2013. Development of inhibitors of the PAS-B domain of the HIF-2a transcription factor. Journal of Medicinal Chemistry 56:1739–1747. doi: 10.1021/jm301847z
62. Rózanowska M, Jarvis-Evans J, Korytowski W, Boulton ME, Burke JM, Sarna T. 1995. Blue light-induced reactivity of retinal age pigment. in vitro generation of oxygen-reactive species. The Journal of Biological Chemistry 270: 18825–18830. doi: 10.1074/jbc.270.32.18825
63. Rudolf M, Clark ME, Chimento MF, Li CM, Medeiros NE, Curcio CA. 2008. Prevalence and morphology of druse types in the macula and periphery of eyes with age-related maculopathy. Investigative Ophthalmology & Visual Science 49:1200–1209. doi: 10.1167/iovs.07-1466
64. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS. 2000. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Research 60:4010–4015.
65. Sagone AL, Lawrence T, Balcerzak SP. 1973. Effect of smoking on tissue oxygen supply. Blood 41:845–851.
66. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA. 2009. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proceedings of the National Academy of Sciences of the United States of America 106:18751–18756. doi: 10.1073/pnas.0905010106
67. Santos CR, Schulze A, cancer Lipid metabolism in. 2012. Lipid metabolism in cancer. The FEBS Journal 279: 2610–2623. doi: 10.1111/j.1742-4658.2012.08644.x
68. Sarks SH. 1976. Ageing and degeneration in the macular region: a clinico-pathological study. The British Journal of Ophthalmology 60:324–341. doi: 10.1136/bjo.60.5.324
69. Sarks JP, Sarks SH, Killingsworth MC. 1988. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 2 (Pt 5):552–577. doi: 10.1038/eye.1988.106
70. Sarks S, Cherepanoff S, Killingsworth M, Sarks J. 2007. Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration. Investigative Ophthalmology & Visual Science 48:968–977. doi: 10.1167/iovs.06-0443
71. Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK. 2013. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nature Chemical Biology 9:271–276. doi: 10.1038/nchembio.1185
72. Schütt F, Davies S, Kopitz J, Holz FG, Boulton ME. 2000. Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Investigative Ophthalmology & Visual Science 41:2303–2308.
73. Semenza GL. 2009. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Seminars in Cancer Biology 19:12–16. doi: 10.1016/j.semcancer.2008.11.009
74. Semenza GL. 2011. Oxygen sensing, homeostasis, and disease. The New England Journal of Medicine 365:537–547. doi: 10.1056/NEJMra1011165
75. Sheraidah G, Steinmetz R, Maguire J, Pauleikhoff D, Marshall J, Bird AC. 1993. Correlation between lipids extracted from Bruch’s membrane and age. Ophthalmology 100:47–51. doi: 10.1016/s0161-6420(13)31712-6
76. Sheridan CM, Pate S, Hiscott P, Wong D, Pattwell DM, Wong D. 2009. Expression of hypoxia-inducible factor-1alpha and-2alpha in human choroidal neovascular membranes. Graefe’s Archive for Clinical and Experimental Ophthalmology 247:1361–1367. doi: 10.1007/s00417-009-1133-3
77. Sohrab M, Wu K, Fawzi AA. 2012. A pilot study of morphometric analysis of choroidal vasculature in vivo, using en face optical coherence tomography. PloS One 7:e48631. doi: 10.1371/journal.pone.0048631
78. Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, Munnich A, Kaplan J, Coscas G, Soubrane G. 1998. The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. American Journal of Ophthalmology 125:353–359. doi: 10.1016/s0002-9394(99)80146-9
79. Sparrow JR, Parish CA, Hashimoto M, Nakanishi K. 1999. A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture. Investigative Ophthalmology & Visual Science 40:2988–2995.
80. Sparrow JR, Nakanishi K, Parish CA. 2000. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Investigative Ophthalmology & Visual Science 41:1981–1989.
81. Spraul CW, Lang GE, Grossniklaus HE. 1996. Morphometric analysis of the choroid, Bruch’s membrane, and retinal pigment epithelium in eyes with age-related macular degeneration. Investigative Ophthalmology & Visual Science 37:2724–2735.
82. Spraul CW, Lang GE, Grossniklaus HE, Lang GK. 1999. Histologic and morphometric analysis of the choroid, Bruch’s membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Survey of Ophthalmology 44 Suppl 1:S10–32. doi: 10.1016/s0039-6257(99)00086-7
83. Starita C, Hussain AA, Marshall J. 1995. Decreasing hydraulic conductivity of Bruch’s membrane: relevance to photoreceptor survival and lipofuscinoses. American Journal of Medical Genetics 57:235–237. doi: 10.1002/ajmg.1320570224
84. Starita C, Hussain AA, Pagliarini S, Marshall J. 1996. Hydrodynamics of ageing Bruch’s membrane: implications for macular disease. Experimental Eye Research 62:565–572. doi: 10.1006/exer.1996.0066
85. Starita C, Hussain AA, Patmore A, Marshall J. 1997. Localization of the site of major resistance to fluid transport in Bruch’s membrane. Investigative Ophthalmology & Visual Science 38:762–767.
86. Strauss O. 2005. The retinal pigment epithelium in visual function. Physiological Reviews 85:845–881. doi: 10.1152/physrev.00021.2004
87. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T. 2010. Regulation of the hif-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7:391–402. doi: 10.1016/j.stem.2010.06.020
88. Tamai K, Spaide RF, Ellis EA, Iwabuchi S, Ogura Y, Armstrong D. 2002. Lipid hydroperoxide stimulates subretinal choroidal neovascularization in the rabbit. Experimental Eye Research 74:301–308. doi: 10.1006/exer.2001.1121
89. Tautenhahn R, Patti GJ, Rinehart D, Siuzdak G. 2012a. XCMS Online: a web-based platform to process untargeted metabolomic data. Analytical Chemistry 84:5035–5039. doi: 10.1021/ac300698c
90. Tautenhahn R, Cho K, Uritboonthai W, Zhu Z, Patti GJ, Siuzdak G. 2012b. An accelerated workflow for untargeted metabolomics using the METLIN database. Nature Biotechnology 30:826–828. doi: 10.1038/nbt.2348
91. von Rückmann A, Fitzke FW, Bird AC. 1997. Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope. Investigative Ophthalmology & Visual Science 38:478–486. doi: 10.1136/bjo.82.4.346
92. Wang L, Clark ME, Crossman DK, Kojima K, Messinger JD, Mobley JA, Curcio CA. 2010. Abundant lipid and protein components of drusen. PloS One 5:e10329. doi: 10.1371/journal.pone.0010329
93. Warburg O. 1956. On the origin of cancer cells. Science 123:309–314. doi: 10.1126/science.123.3191.309
94. Wolter JR, Falls HF. 1962. Bilateral confluent drusen. ArchArchives Ophthalmolof Ophthalmology 68:219–226. doi: 10.1001/archopht.1962.00960030223013
95. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY. 2014. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet. Global Health 2:e106–116. doi: 10.1016/S2214-109X(13)70145-1
96. Zarbin MA. 1998. Age-related macular degeneration: review of pathogenesis. European Journal of Ophthalmology 8:199–206.
97. Zerbib J, Seddon JM, Richard F, Reynolds R, Leveziel N, Benlian P, Borel P, Feingold J, Munnich A, Soubrane G, Kaplan J, Rozet JM, Souied EH. 2009. rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration. PloS One 4:e7341. doi: 10.1371/journal.pone.0007341
98. Zhang L, Buitendijk GHS, Lee K, Sonka M, Springelkamp H, Hofman A, Vingerling JR, Mullins RF, Klaver CCW, Abràmoff MD. 2015. Validity of Automated Choroidal Segmentation in SS-OCT and SD-OCT. Investigative Ophthalmology & Visual Science 56:3202–3211. doi: 10.1167/iovs.14-15669
99. Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, LaVail MM, Vollrath D. 2011. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. The Journal of Clinical Investigation 121:369–383. doi: 10.1172/JCI44303
100. Zhao J, Du F, Shen G, Zheng F, Xu B. 2015. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death & Disease 6:e1600. doi: 10.1038/cddis.2014.565
101. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. 2010. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 117:303 e1. doi: 10.1016/j.ophtha.2009.07.014