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Journal of Diabetes & Metabolic Disorders

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01-12-2020 | Diabetic Retinopathy | Research article

Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome

Authors: Ambrose Teru Patrick, Weilue He, Joshua Madu, Srinivas R. Sripathi, Seulggie Choi, Kook Lee, Faith Pwaniyibo Samson, Folami L. Powell, Manuela Bartoli, Donghyun Jee, Diana R. Gutsaeva, Wan Jin Jahng

Published in: Journal of Diabetes & Metabolic Disorders | Issue 2/2020

Abstract

Purpose

The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models.

Methods

We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used.

Results

We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue.

Conclusions

Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR.

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Pusparajah P, Lee LH, Kadir KA. Molecular markers of diabetic retinopathy: Potential screening tool of the future? Front Physiol. 2016;7:1–19. https://doi.org/10.3389/fphys.2016.00200.CrossRef

VanGuilder HD, Bixler GV, Kutzler L, Brucklacher RM, Bronson SK, Kimball SR, Freeman WM. Multi-modal proteomic analysis of retinal protein expression alterations in a rat model of diabetic retinopathy. PLoS One. 2011;6:e16271. https://doi.org/10.1371/journal.pone.0016271.CrossRefPubMedPubMedCentral

Kuo JZ, Wong TY, Rotter JI, Wiggs JL. Challenges in elucidating the genetics of diabetic retinopathy. JAMA Ophthalmol. 2014;132:96–107. https://doi.org/10.1001/jamaophthalmol.2013.5024.CrossRefPubMedPubMedCentral

Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30:343–58. https://doi.org/10.1016/j.preteyeres.2011.05.002.CrossRefPubMedPubMedCentral

Petrovič D. Candidate genes for proliferative diabetic retinopathy. Biomed Res Int 2013;2013:1–9. https://doi.org/10.1155/2013/540416.

Ly A, Scheerer MF, Zukunft S, Muschet C, Merl J, Adamski J, Hrabě M, De Angelis S, Neschen SM, Hauck M, Ueffing. Retinal proteome alterations in a mouse model of type 2 diabetes. Diabetologia. 2014;57:192–203. https://doi.org/10.1007/s00125-013-3070-2.CrossRefPubMed

Decanini A, Karunadharma PR, Nordgaard CL, Feng X, Olsen TW, Ferrington DA. Human retinal pigment epithelium proteome changes in early diabetes. Diabetologia. 2008;51:1051–61. https://doi.org/10.1007/s00125-008-0991-2.CrossRefPubMedPubMedCentral

Shah SS, Tsang SH, Mahajan VB. Erythropoetin receptor expression in the human diabetic retina. BMC Res Notes. 2009;2:234. https://doi.org/10.1186/1756-0500-2-234.CrossRefPubMedPubMedCentral

Caprara C, Grimm C. From oxygen to erythropoietin: relevance of hypoxia for retinal development, health and disease. Prog Retin Eye Res. 2012;31:89–119. https://doi.org/10.1016/j.preteyeres.2011.11.003.CrossRefPubMed

10.

Schrier SA, Falk MJ. Mitochondrial disorders and the eye. Curr Opin Ophthalmol. 2011;22:325–31. https://doi.org/10.1097/ICU.0b013e328349419d.CrossRefPubMedPubMedCentral

11.

Mishra M, Kowluru RA. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy. Investig Ophthalmol Vis Sci. 2015;56:5133–42. https://doi.org/10.1167/iovs.15-16937.CrossRef

12.

Rajala A, Gupta VK, Anderson RE, Rajala RVS. Light activation of the insulin receptor regulates mitochondrial hexokinase. A possible mechanism of retinal neuroprotection. Mitochondrion. 2013;13:566–76. https://doi.org/10.1016/j.mito.2013.08.005.CrossRefPubMed

13.

Fort PE, Freeman WM, Losiewicz MK, Singh RSJ, Gardner TW. The Retinal Proteome in Experimental Diabetic Retinopathy. Mol Cell Proteomics. 2009;8:767–79. https://doi.org/10.1074/mcp.M800326-MCP200.CrossRefPubMedPubMedCentral

14.

Csősz É, Deák E, Kalló G, Csutak A, Tőzsér J. Diabetic retinopathy: Proteomic approaches to help the differential diagnosis and to understand the underlying molecular mechanisms. J Proteomics. 2017;150:351–8. https://doi.org/10.1016/j.jprot.2016.06.034.CrossRefPubMed

15.

Cunha-Vaz JG. Pathophysiology of diabetic retinopathy. Br J Ophthalmol. 1978;62:351–5. https://doi.org/10.1136/bjo.62.6.351.CrossRefPubMedPubMedCentral

16.

Dagher Z, Park YS, Asnaghi V, Hoehn T, Gerhardinger C, Lorenzi M. Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes. 2004;53:2404–11. https://doi.org/10.2337/diabetes.53.9.2404.CrossRefPubMed

17.

Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis. 2015. https://doi.org/10.1016/j.bbadis.2015.08.001. CrossRef

18.

Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. J Biol Chem. 1999;274:23463–7. https://doi.org/10.1074/jbc.274.33.23463. CrossRefPubMed

19.

Chung H, Lee H, Lamoke F, Hrushesky WJM, Wood P, Jahng WJ. Neuroprotective role of erythropoietin by antiapoptosis in the retina. J Neurosci Res. 2009;87:2365–74. https://doi.org/10.1002/jnr.22046.CrossRefPubMedPubMedCentral

20.

Arnouk H, Lee H, Zhang R, Chung H, Hunt RC, Jahng WJ. Early biosignature of oxidative stress in the retinal pigment epithelium. J Proteomics. 2011;74:254–61. https://doi.org/10.1016/j.jprot.2010.11.004.CrossRefPubMed

21.

Zhang R, Hrushesky WJM, Wood P, Lee SH, Hunt RC, Jahng WJ. Melatonin reprogrammes proteomic profile in light-exposed retina in vivo. Int J Biol Macromol. 2010;47:255–60. https://doi.org/10.1016/j.ijbiomac.2010.04.013.CrossRefPubMedPubMedCentral

22.

Sripathi SR, Prigge CL, Elledge B, He W, Offor J, Gutsaeva DR, Jahng WJ. Melatonin modulates prohibitin and cytoskeleton in the retinal pigment epithelium. Int J Sci Eng Res. 2017;8:502–6. https://doi.org/10.14299/ijser.2017.07.001. CrossRefPubMedPubMedCentral

23.

Joshua M, Okere C, Sylvester O, Yahaya M, Precious O, Dluya T, Um J-Y, Neksumi M, Boyd J, Vincent-Tyndall J, Choo D-W, Gutsaeva DR, Jahng WJ. Disruption of angiogenesis by anthocyanin-rich extracts of hibiscus sabdariffa. Int J Sci Eng Res. 2017;8:299–307. https://doi.org/10.14299/ijser.2017.02.009. CrossRefPubMedPubMedCentral

24.

Jahng WJ. New Biomarkers in the Retina and RPE Under Oxidative Stress, in: Adio A, editor, Ocul. Dis., IntechOpen, 2012: pp. 121–155. https://doi.org/10.5772/48785.

25.

He W, Sripathi SR, Joshua M, Zhang R, Tosin F, Ambrose P, Gutsaeva DR, Jahng WJ. Mechanistic dissection of macular degeneration using the phosphorylation interactome, in: Lo G, Giudice, editors, Vis. Impair. Blind., IntechOpen, 2020. https://doi.org/10.5772/intechopen.83016.

26.

Lee H, Arnouk H, Sripathi S, Chen P, Zhang R, Bartoli M, Hunt RC, Hrushesky WJM, Chung H, Lee SH, Jahng WJ. Prohibitin as an oxidative stress biomarker in the eye. Int J Biol Macromol. 2010;47:685–90. https://doi.org/10.1016/j.ijbiomac.2010.08.018.CrossRefPubMedPubMedCentral

27.

Lee H, Chung H, Lee SH, Jahng WJ. Light-induced phosphorylation of crystallins in the retinal pigment epithelium. Int J Biol Macromol. 2011;48:194–201. https://doi.org/10.1016/j.ijbiomac.2010.11.006.CrossRefPubMed

28.

Lee H, Chung H, Arnouk H, Lamoke F, Hunt RC, Hrushesky WJM, Wood PA, Lee SH, Jahng WJ. Cleavage of the retinal pigment epithelium-specific protein RPE65 under oxidative stress. Int J Biol Macromol. 2010;47:104–8. https://doi.org/10.1016/j.ijbiomac.2010.05.014.CrossRefPubMedPubMedCentral

29.

Sripathi SR, He W, Atkinson CL, Smith JJ, Liu Z, Elledge BM, Jahng WJ. Mitochondrial-nuclear communication by prohibitin shuttling under oxidative stress. Biochemistry. 2011;50:8342–51. https://doi.org/10.1021/bi2008933.CrossRefPubMedPubMedCentral

30.

Sripathi SR, He W, Um J, Moser T, Dehnbostel S, Kindt K, Goldman J, Frost MC, Jahng WJ. Nitric oxide leads to cytoskeletal reorganization in the retinal pigment epithelium under oxidative stress. Adv Biosci Biotechnol. 2012;03:1167–78. https://doi.org/10.4236/abb.2012.38143.CrossRef

31.

Sripathi SR, Sylvester O, He W, Moser T, Um J, Lamoke F, Ramakrishna W, Bernstein PS, Bartoli M, Jahng WJ. Prohibitin as the molecular binding switch in the retinal pigment epithelium. Protein J. 2016;35:1–16. https://doi.org/10.1007/s10930-015-9641-y. CrossRefPubMedPubMedCentral

32.

Sripathi SR, He W, Sylvester O, Neksumi M, Um J-Y, Dluya T, Bernstein PS, Jahng WJ. Altered cytoskeleton as a mitochondrial decay signature in the retinal pigment epithelium. Protein J. 2016;35:179–92. https://doi.org/10.1007/s10930-016-9659-9. CrossRefPubMedPubMedCentral

33.

Sripathi S, He W, Prigge CL, Sylvester O, Um J-Y, Powell FL, Neksumi M, Bernstein PS, Choo D-W, Bartoli M, Gutsaeva DR, Jahng WJ. Interactome mapping guided by tissue-specific phosphorylation in age-related macular degeneration. Int J Sci Eng Res. 2017;8:680–98. https://doi.org/10.14299/ijser.2017.02.010. CrossRefPubMedPubMedCentral

34.

Ponce J, Brea D, Carrascal M, Guirao VV, Degregorio-Rocasolano N, Sobrino TT, Castillo JJ, Davalos A, Gasull T, Dávalos A, Gasull T. The effect of simvastatin on the proteome of detergent-resistant membrane domains: decreases of specific proteins previously related to cytoskeleton regulation, calcium homeostasis and cell fate. Proteomics. 2010;10:1954–65. https://doi.org/10.1002/pmic.200900055.CrossRefPubMed

35.

Dong P, Flores J, Pelton K, Solomon KR. Prohibitin is a cholesterol-sensitive regulator of cell cycle transit. J Cell Biochem. 2010;111:1367–74. https://doi.org/10.1002/jcb.22865.CrossRefPubMed

36.

Kowluru RA, Santos JM, Zhong Q. Sirt1, A negative regulator of matrix metalloproteinase-9 in diabetic retinopathy. Investig Ophthalmol Vis Sci. 2014;55:5653–60. https://doi.org/10.1167/iovs.14-14383. CrossRef

37.

Pusparajah P, Lee LH, Kadir KA. Molecular markers of diabetic retinopathy: Potential screening tool of the future? Front Physiol. 2016. https://doi.org/10.3389/fphys.2016.00200.CrossRefPubMedPubMedCentral

38.

Liyanage VRB, Jarmasz JS, Murugeshan N, Bigio MRD, Rastegar M, Davie DNA Jr. modifications: Function and applications in normal and disease states. Biology (Basel). 2014;3(4):670–723. https://doi.org/10.3390/biology3040670. CrossRef

39.

Jin J, Min H, Kim SJ, Oh S, Kim K, Yu HG, Park T, Kim Y. Development of diagnostic biomarkers for detecting diabetic retinopathy at early stages using quantitative proteomics. J Diabetes Res. 2016;2016:6571976. https://doi.org/10.1155/2016/6571976. CrossRefPubMed

40.

Nalefski EA, Falke JJ. The C2 domain calcium-binding motif: Structural and functional diversity. Protein Sci. 1996;5:2375–90. https://doi.org/10.1002/pro.5560051201. CrossRefPubMedPubMedCentral

41.

Venhoranta H, Bauersachs S, Taponen J, Lohi H, Taira T, Andersson M, Kind A, Schnieke A, Flisikowski K. Fetal growth restriction caused by MIMT1 deletion alters brain transcriptome in cattle. Int J Dev Neurosci. 2013;31:463–7. https://doi.org/10.1016/j.ijdevneu.2013.05.003.CrossRefPubMed

42.

Zou B, Liu X, Gong Y, Cai C, Li P, Xing S, Pokhrel B, Zhang B, Li J. A novel 12-marker panel of cancer-associated fibroblasts involved in progression of hepatocellular carcinoma. Cancer Manag Res. 2018;10:5303–11. https://doi.org/10.2147/CMAR.S176152. CrossRefPubMedPubMedCentral

43.

Zhu R, Cheng M, Lu T, Yang N, Ye S, Pan Y-H, Hong T, Dang S, Zhang W. A disintegrin and metalloproteinase with thrombospondin motifs 18 deficiency leads to visceral adiposity and associated metabolic syndrome in mice. Am J Pathol. 2018;188:461–73. https://doi.org/10.1016/j.ajpath.2017.10.020. CrossRefPubMed

44.

Shalaby L, Thounaojam M, Tawfik A, Li J, Hussein K, Jahng WJ, Al-Shabrawey M, Kwok HF, Bartoli M, Gutsaeva D. Role of endothelial ADAM17 in early vascular changes associated with diabetic retinopathy. J Clin Med. 2020;9:400. https://doi.org/10.3390/jcm9020400. CrossRefPubMedCentral

45.

Brockhaus K, Melkonyan H, Prokosch-Willing V, Liu H, Thanos S. Alterations in tight- and adherens-junction proteins related to glaucoma mimicked in the organotypically cultivated mouse retina under elevated pressure. Investig Opthalmol Vis Sci. 2020;61:46. https://doi.org/10.1167/iovs.61.3.46. CrossRef

46.

Nita M, Grzybowski A, Ascaso FJ, Huerva V. Age-related macular degeneration in the aspect of chronic low-grade inflammation (Pathophysiological paraInflammation). Mediat Inflamm. 2014;2014:1–10. https://doi.org/10.1155/2014/930671. CrossRef

47.

Livne-Bar I, Lam S, Chan D, Guo X, Askar I, Nahirnyj A, Flanagan JG, Sivak JM. Pharmacologic inhibition of reactive gliosis blocks TNF-α-mediated neuronal apoptosis. Cell Death Dis. 2016. https://doi.org/10.1038/cddis.2016.277.CrossRefPubMedPubMedCentral

48.

Arsenijevic Y, Taverney N, Kostic C, Tekaya M, Riva F, Zografos L, Schorderet D, Munier F. Non-neural regions of the adult human eye: A potential source of neurons? Investig Ophthalmol Vis Sci. 2003. https://doi.org/10.1167/iovs.02-0267.CrossRef

49.

Shinoda K, Hirakata A, Hida T, Yamaguchi Y, Fukuda M, Maekawa S, Azuma N, Ultrastructural and immunohistochemical findings in five patients with vitreomacular traction syndrome, Retina. 2000. https://doi.org/10.1097/00006982-200003000-00011.

50.

Viewer GD. Fam81b family with sequence similarity 81, member B [Rattus norvegicus (Norway rat)]. 2019;3:1–5.

51.

Ramirez-Ardila DE, Ruigrok-Ritstier K, Helmijr JC, Look MP, van Laere S, Dirix L, Berns EMJJ, Jansen MPHM. LRG1 mRNA expression in breast cancer associates with PIK3CA genotype and with aromatase inhibitor therapy outcome. Mol Oncol. 2016;10:1363–73. https://doi.org/10.1016/j.molonc.2016.07.004.CrossRefPubMedPubMedCentral

52.

Nogales E. Structural insights into microtubule function. Annu Rev Biochem. 2000;69:277–302. https://doi.org/10.1146/annurev.biochem.69.1.277. CrossRefPubMed

53.

Eckmiller MS. Renewal of the ciliary axoneme in cone outer segments of the retina of Xenopus laevis. Cell Tissue Res. 1996;285:165–9. https://doi.org/10.1007/s004410050632. CrossRefPubMed

54.

Gong J, Sagiv O, Cai H, Tsang SH, Del LV, Priore. Effects of extracellular matrix and neighboring cells on induction of human embryonic stem cells into retinal or retinal pigment epithelial progenitors. Exp Eye Res. 2008;86:957–65. https://doi.org/10.1016/j.exer.2008.03.014. CrossRefPubMedPubMedCentral

55.

Goldenberg-Cohen N, Avraham-Lubin B-CR, Sadikov T, Goldstein RS, Askenasy N. Primitive stem cells derived from bone marrow express glial and neuronal markers and support revascularization in injured retina exposed to ischemic and mechanical damage. Stem Cells Dev. 2012;21:1488–500. https://doi.org/10.1089/scd.2011.0366. CrossRefPubMed

56.

Struebing FL, Lee RK, Williams RW, Geisert EE. Genetic networks in mouse retinal ganglion cells. Front Genet. 2016;7:169. https://doi.org/10.3389/fgene.2016.00169. CrossRefPubMedPubMedCentral

57.

Loukovaara S, Sandholm J, Aalto K, Liukkonen J, Jalkanen S, Yegutkin GG. Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy. J Mol Med. 2017;95:193–204. https://doi.org/10.1007/s00109-016-1472-6.CrossRefPubMed

58.

Loukovaara S, Sahanne S, Jalkanen S, Yegutkin GG. Increased intravitreal adenosine 5′-triphosphate, adenosine 5′-diphosphate and adenosine 5′-monophosphate levels in patients with proliferative diabetic retinopathy. Acta Ophthalmol. 2015;93:67–73. https://doi.org/10.1111/aos.12507.CrossRefPubMed

59.

Du Y, Veenstra A, Palczewski K, Kern TS. Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci. 2013;110:16586–91. https://doi.org/10.1073/pnas.1314575110. CrossRefPubMed

60.

Schlotterer A, Kolibabka M, Lin J, Acunman K, Dietrichá N, Sticht C, Fleming T, Nawroth P, Hammes H-P. Methylglyoxal induces retinopathy-type lesions in the absence of hyperglycemia: studies in a rat model. FASEB J. 2019;33:4141–53. https://doi.org/10.1096/fj.201801146RR.CrossRefPubMed

61.

Acute FPE Complications C. Diabetes. 2011;60:A133–95. https://doi.org/10.2337/db11-478-715.

62.

Zamora DO, Riviere M, Choi D, Pan Y, Planck SR, Rosenbaum JT, David LL, Smith JR. Proteomic profiling of human retinal and choroidal endothelial cells reveals molecular heterogeneity related to tissue of origin. Mol Vis. 2007;13:2058–65. http://www.ncbi.nlm.nih.gov/pubmed/18079679.

63.

Devi TS, Yumnamcha T, Yao F, Somayajulu M, Kowluru RA, Singh LP. TXNIP mediates high glucose-induced mitophagic flux and lysosome enlargement in human retinal pigment epithelial cells. Biol Open. 2019;8:bio038521. https://doi.org/10.1242/bio.038521.CrossRefPubMedPubMedCentral

64.

Yamane K, Minamoto A, Yamashita H, Takamura H, Miyamoto-Myoken Y, Yoshizato K, Nabetani T, Tsugita A, Mishima HK. Proteome analysis of human vitreous proteins. Mol Cell Proteomics. 2003;2:1177–87. https://doi.org/10.1074/mcp.M300038-MCP200. CrossRefPubMed

65.

Garcia-Ramírez M, Hernández C, Villarroel M, Canals F, Alonso MA, Fortuny R, Masmiquel L, Navarro A, García-Arumí J, Simó R. Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy. Diabetologia. 2009;52:2633–41. https://doi.org/10.1007/s00125-009-1548-8.CrossRefPubMed

66.

Minamoto A, Yamane K, Yokoyama T. Proteomics of Vitreous Fluid. In: Proteomics Hum Body Fluids. Totowa: Humana Press; 2007. p. 495–507. https://doi.org/10.1007/978-1-59745-432-2_23.

67.

Kang M-K, Lee E-J, Kim Y-H, Kim D, Oh H, Kim S-I, Kang Y-H. Chrysin ameliorates malfunction of retinoid visual cycle through blocking activation of AGE-RAGE-ER stress in glucose-stimulated retinal pigment epithelial cells and diabetic eyes. Nutrients. 2018;10:1046. https://doi.org/10.3390/nu10081046. CrossRefPubMedCentral

68.

Goldstein AS, Witte ON. A plethora of progenitors in the post-natal prostate. EMBO Rep. 2012. https://doi.org/10.1038/embor.2012.169.CrossRefPubMedPubMedCentral

69.

Fisher JW. Landmark advances in the development of erythropoietin. Exp Biol Med (Maywood). 2010;235:1398–411. https://doi.org/10.1258/ebm.2010.010137.CrossRef

70.

Wu T, Handa JT, Gottsch JD. Light-induced oxidative stress in choroidal endothelial cells in mice. Invest Ophthalmol Vis Sci. 2005;46:1117–23. https://doi.org/10.1167/iovs.04-0517.CrossRefPubMed

71.

Jarajapu YPR, Cai J, Yan Y, Li Calzi S, Kielczewski JL, Hu P, Shaw LC, Firth SM, Chan-Ling T, Boulton ME, Baxter RC, Grant MB. Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3. PLoS One. 2012;7:e39398. https://doi.org/10.1371/journal.pone.0039398. CrossRefPubMedPubMedCentral

72.

Moreira PI, Santos MS, Moreno AM, Proenca T, Seica R, Oliveira CR. Effect of streptozotocin-induced diabetes on rat brain mitochondria. J Neuroendocrinol. 2004;16:32–8. https://doi.org/10.1111/j.1365-2826.2004.01107.x. CrossRefPubMed

73.

Alam NM, Mills WC, Wong AA, Douglas RM, Szeto HH, Prusky GT. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis Model Mech. 2015;8:701–10. https://doi.org/10.1242/dmm.020248. CrossRefPubMedPubMedCentral

74.

Gargiulo P, Goldberg J, Romani B, Schiaffini R, Ciampalini P, Faulk WP, McIntyre JA. Qualitative and quantitative studies of autoantibodies to phospholipids in diabetes mellitus. Clin Exp Immunol. 1999;118:30–4. https://doi.org/10.1046/j.1365-2249.1999.01014.x. CrossRefPubMedPubMedCentral

75.

Gerl VB, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, Bhakdi S. Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Investig Ophthalmol Vis Sci. 2002;43:1104–8. https://iovs.arvojournals.org/article.aspx?articleid=2200162.

76.

Liu X, Mameza MG, Lee YS, Eseonu CI, Yu C-R, Kang Derwent JJ, Egwuagu CE. Suppressors of cytokine-signaling proteins induce insulin resistance in the retina and promote survival of retinal cells. Diabetes. 2008;57:1651–8. https://doi.org/10.2337/db07-1761. CrossRefPubMedPubMedCentral

77.

del Olmo-Aguado S, Núñez-Álvarez C, Osborne NN. Blue light action on mitochondria leads to cell death by necroptosis. Neurochem Res. 2016;41:2324–35. https://doi.org/10.1007/s11064-016-1946-5. CrossRefPubMed

78.

Ren X, Lu H, Wang N, Zhang C, Ji Y, Cui S, Dong Y, Yang K, Du M, Diao F, Kong L. Thioredoxin is implicated in the anti-apoptotic effects of grape seed proanthocyanidin extract during hyperglycemia. Mol Med Rep. 2017;16:7731–7. https://doi.org/10.3892/mmr.2017.7508.CrossRefPubMed

79.

Kim SS, Utsunomiya H, Koski J, Wu BM, Cima MJ, Sohn J, Mukai K, Griffith LG, Vacanti JP. Survival and function of hepatocytes on a novel three-dimensional synthetic biodegradable polymer scaffold with an intrinsic network of channels. Ann Surg. 1998;228:8–13. https://doi.org/10.1097/00000658-199807000-00002.CrossRefPubMedPubMedCentral

80.

Pang C, Jia L, Jiang S, Liu W, Hou X, Zuo Y, Gu H, Bao Y, Wu Q, Xiang K, Gao X, Jia W. Determination of diabetic retinopathy prevalence and associated risk factors in Chinese diabetic and pre-diabetic subjects: Shanghai diabetic complications study. Diabetes Metab Res Rev. 2012;28:276–83. https://doi.org/10.1002/dmrr.1307. CrossRefPubMed

81.

Sheetz MJ. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA. 2002;288:2579. https://doi.org/10.1001/jama.288.20.2579. CrossRefPubMed

82.

Popova EA, Mironova RS, Odjakova MK. Non-enzymatic glycosylation and deglycating enzymes. Biotechnol Biotechnol Equip. 2010;24:1928–35. https://doi.org/10.2478/V10133-010-0066-7. CrossRef

83.

Pacher P, Szabó C. Role of poly(ADP-Ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme. Antioxid Redox Signal. 2005;7:1568–80. https://doi.org/10.1089/ars.2005.7.1568. CrossRefPubMedPubMedCentral

84.

Kiss L, Szabó C. The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity. Mem Inst Oswaldo Cruz. 2005;100:29–37. https://doi.org/10.1590/S0074-02762005000900007. CrossRefPubMed

85.

Warboys CM, Fraser PA. Hyperglycemia attenuates acute permeability response to advanced glycation end products in retinal microvasculature. Microvasc Res. 2010;80:174–6. https://doi.org/10.1016/j.mvr.2010.03.004.CrossRefPubMed

86.

Lind KR, Ball KK, Cruz NF, Dienel GA. The unfolded protein response to endoplasmic reticulum stress in cultured astrocytes and rat brain during experimental diabetes. Neurochem Int. 2013;62:784–95. https://doi.org/10.1016/j.neuint.2013.02.009.CrossRefPubMedPubMedCentral

87.

Eljarrat-Binstock E, Raiskup F, Stepensky D, Domb AJ, Frucht-Pery J. Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis. Investig Opthalmology Vis Sci. 2004;45:2543. https://doi.org/10.1167/iovs.03-1294. CrossRef

88.

Huang SP, Palla S, Ruzycki P, Varma RA, Harter T, Reddy GB, Petrash JM. Aldo-keto reductases in the eye. J Ophthalmol. 2010;2010:1–6. https://doi.org/10.1155/2010/521204. CrossRef

89.

Kawanishi K, Ueda H, Moriyasu M. Aldose reductase inhibitors from the nature. Curr Med Chem. 2003;10:1353–74. https://doi.org/10.2174/0929867033457304. CrossRefPubMed

90.

Kumar H, Shah A, Sobhia ME. Novel insights into the structural requirements for the design of selective and specific aldose reductase inhibitors. J Mol Model. 2012;18:1791–9. https://doi.org/10.1007/s00894-011-1195-0.CrossRefPubMed

91.

Veeresham C, Swetha E, Rao AR, Asres K. Vitro and in vivo aldose reductase inhibitory activity of standardized extracts and the major constituent of andrographis paniculata. Phyther Res. 2013;27:412–6. https://doi.org/10.1002/ptr.4722. CrossRef

92.

Zhan X, Du Y, Crabb JS, Gu X, Kern TS, Crabb JW. Targets of tyrosine nitration in diabetic rat retina. Mol Cell Proteomics. 2008;7:864–74. https://doi.org/10.1074/mcp.M700417-MCP200.CrossRefPubMedPubMedCentral

93.

Toda N, Nakanishi-Toda M. Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy. Prog Retin Eye Res. 2007;26:205–38. https://doi.org/10.1016/j.preteyeres.2007.01.004.CrossRefPubMed

94.

Gao B-B, Phipps JA, Bursell D, Clermont AC, Feener EP. Angiotensin AT1 receptor antagonism ameliorates murine retinal proteome changes induced by diabetes. J Proteome Res. 2009;8:5541–9. https://doi.org/10.1021/pr9006415. CrossRefPubMedPubMedCentral

95.

Zhang J, Wu Y, Jin Y, Ji F, Sinclair SH, Luo Y, Xu G, Lu L, Dai W, Yanoff M, Li W, Xu G-T. Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes. Invest Ophthalmol Vis Sci. 2008;49:732–42. https://doi.org/10.1167/iovs.07-0721.CrossRefPubMed

96.

Huang Y-C, Lin J-M, Lin H-J, Chen C-C, Chen S-Y, Tsai C-H, Tsai F-J. Genome-wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology. 2011;118:642–8. https://doi.org/10.1016/j.ophtha.2010.07.020. CrossRefPubMed

97.

Qin G, Mallik S, Mitra R, Li A, Jia P, Eischen CM, Zhao Z. MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors. Sci Rep. 2020;10:852. https://doi.org/10.1038/s41598-020-57834-w.CrossRefPubMedPubMedCentral

98.

Miller SFC, Summerhurst K, Rünker AE, Kerjan G, Friedel RH, Chédotal A, Murphy P, Mitchell KJ. Expression of Plxdc2/TEM7R in the developing nervous system of the mouse. Gene Expr Patterns. 2007;7:635–44. https://doi.org/10.1016/j.modgep.2006.12.002.CrossRefPubMed

99.

Perrone L, Devi TS, Hosoya K, Terasaki T, Singh LP. Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions. J Cell Physiol. 2009;221:262–72. https://doi.org/10.1002/jcp.21852.CrossRefPubMed

100.

Abhary S, Hewitt AW, Burdon KP, Craig JE. A systematic meta-analysis of genetic association studies for diabetic retinopathy. Diabetes. 2009;58:2137–47. https://doi.org/10.2337/db09-0059. CrossRefPubMedPubMedCentral

101.

Simões MJ, Lobo C, Egas C, Nunes S, Carmona S, Costa M, Duarte T, Ribeiro L, Faro C, Cunha-Vaz JG. Genetic variants in ICAM1, PPARGC1A and MTHFR are potentially associated with different phenotypes of diabetic retinopathy. Ophthalmologica. 2014;232:156–62. https://doi.org/10.1159/000365229. CrossRefPubMed

102.

Kowluru RA. Role of matrix metalloproteinase-9 in the development of diabetic retinopathy and its regulation by H-Ras. Investig Opthalmology Vis Sci. 2010;51:4320. https://doi.org/10.1167/iovs.09-4851. CrossRef

103.

Mishra M, Flaga J, Kowluru RA. Molecular mechanism of transcriptional regulation of matrix metalloproteinase-9 in diabetic retinopathy. J Cell Physiol. 2016;231:1709–18. https://doi.org/10.1002/jcp.25268. CrossRefPubMed

104.

Kinnunen K, Puustjarvi T, Terasvirta M, Nurmenniemi P, Heikura T, Laidinen S, Paavonen T, Uusitalo H, Yla-Herttuala S. Differences in retinal neovascular tissue and vitreous humour in patients with type 1 and type 2 diabetes. Br J Ophthalmol. 2009;93:1109–15. https://doi.org/10.1136/bjo.2008.148841.CrossRefPubMed

105.

GUSTAVSSON C, AGARDH C-D, HAGERT P, AGARDH E. Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion. Retina. 2008;28:645–52. https://doi.org/10.1097/IAE.0b013e31815ec32d. CrossRefPubMed

106.

Azcutia V, Abu-Taha M, Romacho T, Vázquez-Bella M, Matesanz N, Luscinskas FW, Rodríguez-Mañas L, Sanz MJ, Sánchez-Ferrer CF, Peiró C. Inflammation determines the pro-adhesive properties of high extracellular d-glucose in human endothelial cells in vitro and rat microvessels in vivo. PLoS One. 2010;5:e10091. https://doi.org/10.1371/journal.pone.0010091. CrossRefPubMedPubMedCentral

107.

Xie M, Hu A, Luo Y, Sun W, Hu X, Tang S. Interleukin-4 and melatonin ameliorate high glucose and interleukin-1β stimulated inflammatory reaction in human retinal endothelial cells and retinal pigment epithelial cells. Mol Vis. 2014;20:921–8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077596/.

108.

Arjamaa O, Nikinmaa M. Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res. 2006;83:473–83. https://doi.org/10.1016/j.exer.2006.01.016.CrossRefPubMed

109.

Loukovaara S, Koivunen P, Inglés M, Escobar J, Vento M, Andersson S. Elevated protein carbonyl and HIF-1α levels in eyes with proliferative diabetic retinopathy. Acta Ophthalmol. 2014;92:323–7. https://doi.org/10.1111/aos.12186.CrossRefPubMed

110.

Abu-El-Asrar AM, Dralands L, Missotten L, Al-Jadaan I, Geboes K. Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci. 2004;45:2760–6. https://doi.org/10.1167/iovs.03-1392.CrossRefPubMed

111.

Shevchenko AV, Prokofiev VF, Konenkov VI, Klimontov VV, Tyan NV, Chernykh DV, Trunov AN, Chernykh VV. Polymorphisms of extracellular connective tissue remodeling proteinases and MMP2, MMP3, MMP9 genes, and neoangigenesis VEGF gene in retinal microangiopathy in the patients with type 2 diabetes mellitus. Med Immunol. 2019;21:441–50. https://doi.org/10.15789/1563-0625-2019-3-441-450.CrossRef

112.

Karumanchi DK, Gaillard ER, Dillon J. Early diagnosis of diabetes through the eye. Photochem Photobiol. 2015;91:1497–504. https://doi.org/10.1111/php.12524. CrossRefPubMed

113.

Lyons TJ, Basu A. Biomarkers in diabetes: hemoglobin A1c, vascular and tissue markers. Transl Res. 2012;159:303–12. https://doi.org/10.1016/j.trsl.2012.01.009.CrossRefPubMedPubMedCentral

114.

Laíns I, Gantner M, Murinello S, Lasky-Su JA, Miller JW, Friedlander M, Husain D. Metabolomics in the study of retinal health and disease. Prog Retin Eye Res. 2019;69:57–79. https://doi.org/10.1016/j.preteyeres.2018.11.002.CrossRefPubMed

115.

Rhee SY, Jung ES, Park HM, Jeong SJ, Kim K, Chon S, Yu S-Y, Woo J-T, Lee CH. Plasma glutamine and glutamic acid are potential biomarkers for predicting diabetic retinopathy. Metabolomics. 2018;14:89. https://doi.org/10.1007/s11306-018-1383-3.CrossRefPubMedPubMedCentral

116.

Paris LP, Johnson CH, Aguilar E, Usui Y, Cho K, Hoang LT, Feitelberg D, Benton HP, Westenskow PD, Kurihara T, Trombley J, Tsubota K, Ueda S, Wakabayashi Y, Patti GJ, Ivanisevic J, Siuzdak G, Friedlander M. Global metabolomics reveals metabolic dysregulation in ischemic retinopathy. Metabolomics. 2016;12:15. https://doi.org/10.1007/s11306-015-0877-5.CrossRefPubMed

117.

Haines NR, Manoharan N, Olson JL, D’Alessandro A, Reisz JA. Metabolomics Analysis of human vitreous in diabetic retinopathy and rhegmatogenous retinal detachment. J Proteome Res. 2018;17:2421–7. https://doi.org/10.1021/acs.jproteome.8b00169. CrossRefPubMed

Title: Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome
Authors: Ambrose Teru Patrick
Weilue He
Joshua Madu
Srinivas R. Sripathi
Seulggie Choi
Kook Lee
Faith Pwaniyibo Samson
Folami L. Powell
Manuela Bartoli
Donghyun Jee
Diana R. Gutsaeva
Wan Jin Jahng
Publication date: 01-12-2020
Publisher: Springer International Publishing
Keywords: Diabetic Retinopathy
Diabetic Retinopathy
Published in: Journal of Diabetes & Metabolic Disorders / Issue 2/2020
Electronic ISSN: 2251-6581
DOI: https://doi.org/10.1007/s40200-020-00570-9

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