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Elevation of the vitreous body concentrations of oxidative stress-responsive apoptosis-inducing protein (ORAIP) in proliferative diabetic retinopathy

  • Yuta Suzuki
  • Takako Yao
  • Ko Okumura
  • Yoshinori SekoEmail author
  • Shigehiko Kitano
Medical Ophthalmology

Abstract

Purpose

Oxidative stress has been implicated in the pathogenesis of various disorders, including diabetic retinopathy (DR). Oxidative stress-responsive apoptosis-inducing protein (ORAIP; a tyrosine-sulfated secreted form of eukaryotic translation initiation factor 5A [eIF5A]) is a recently discovered pro-apoptotic ligand that is secreted from cells in response to oxidative stress and induces apoptosis in an autocrine fashion. This study aimed to determine if ORAIP plays a role in DR.

Methods

To investigate the role of ORAIP in DR, we analyzed the levels of ORAIP in the vitreous body and their relationship with the extent of proliferative diabetic retinopathy (PDR). Enzyme-linked immunosorbent assay was used to quantify the levels of ORAIP, vascular endothelial growth factor (VEGF), C–C motif chemokine ligand 2 (CCL2), interleukin-6 (IL-6), and IL-8 in the vitreous body of 40 eyes from 28 patients with PDR and 11 patients with non-PDR (NPDR). We also analyzed the expression of ORAIP in insoluble proliferative tissues from vitreous body samples by immunofluorescent staining.

Results

The vitreous body concentration of ORAIP was significantly (P = 0.0433) higher in the PDR group (52.26 ± 8.68 [mean ± SE] ng/mL, n = 29) than in the NPDR group (28.21 ± 7.30 ng/mL, n = 11). However, there were no significant correlations between the concentration of ORAIP and those of VEGF, IL-6, CCL2, or IL-8. ORAIP expression was observed in the insoluble proliferative tissues in vitreous body samples of most patients in the PDR group, whereas almost no expression of ORAIP was observed in patients in the NPDR group.

Conclusions

Our findings strongly suggest that ORAIP plays a role in oxidative stress-induced retinal injury and may be a sensitive diagnostic marker and a promising therapeutic target for oxidative stress-induced cytotoxicity.

Keywords

Chemokines Diabetic retinopathy Oxidative stress-responsive apoptosis inducing protein Proliferative diabetic retinopathy Vascular endothelial growth factor Vitreous body 

Notes

Acknowledgements

Editorial support in the form of medical writing was provided by Editage (www.editage.com), a division of Cactus Communications Pvt., Ltd.

Funding

This work was supported by a grant from Takeda Research Support and Novartis Pharma Research Grants and by research support from Alcon Pharma, Senju Pharmaceutical Co. Ltd. and Bayer Pharmaceutical Co., Ltd.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and was approved by the Ethics Committee of Tokyo Women’s Medical University.

Informed consent

Informed written consent was obtained from all patients before ophthalmologic examination.

References

  1. 1.
    Kowluru RA, Kowluru A, Mishra M, Kumar B (2015) Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res 48:40–61.  https://doi.org/10.1016/j.preteyeres.2015.05.001 CrossRefGoogle Scholar
  2. 2.
    Fong DS, Aiello LP, Ferris FL 3rd, Klein R (2004) Diabetic retinopathy. Diabetes Care 27:2540–2553.  https://doi.org/10.2337/diacare.27.10.2540 CrossRefGoogle Scholar
  3. 3.
    Noma H, Funatsu H, Yamashita H, Kitano S, Mishima HK, Hori S (2002) Regulation of angiogenesis in diabetic retinopathy: possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 120:1075–1080.  https://doi.org/10.1001/archopht.120.8.1075 CrossRefGoogle Scholar
  4. 4.
    Nawaz MI, Van Raemdonck K, Mohammad G, Kangave D, Van Damme J, Abu El-Asrar AM, Struyf S (2013) Autocrine CCL2, CXCL4, CXCL9 and CXCL10 signal in retinal endothelial cells and are enhanced in diabetic retinopathy. Exp Eye Res 109:67–76.  https://doi.org/10.1016/j.exer.2013.01.008 CrossRefGoogle Scholar
  5. 5.
    Osaadon P, Fagan XJ, Lifshitz T, Levy J (2014) A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye 28:510–520.  https://doi.org/10.1038/eye.2014.13 CrossRefGoogle Scholar
  6. 6.
    Eshaq RS, Aldalati AMZ, Alexander JS, Harris NR (2017) Diabetic retinopathy: breaking the barrier. Pathophysiology 24:229–241.  https://doi.org/10.1016/j.pathophys.2017.07.001 CrossRefGoogle Scholar
  7. 7.
    Myung SK, Ju W, Cho B, Oh SW, Park SM, Koo BK, Park BJ, Korean Meta-Analysis Study Group (2013) Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. Br Med J 346:f10.  https://doi.org/10.1136/bmj.f10 CrossRefGoogle Scholar
  8. 8.
    Mayer-Davis EJ, Bell RA, Reboussin BA, Rushing J, Marshall JA, Hamman RF (1998) Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley Diabetes Study. Ophthalmology 105:2264–2270.  https://doi.org/10.1016/S0161-6420(98)91227-1 CrossRefGoogle Scholar
  9. 9.
    Seko Y, Fujimura T, Yao T, Taka H, Mineki R, Okumura K, Murayama K (2015) Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis. Sci Rep 5:13737.  https://doi.org/10.1038/srep13737 CrossRefGoogle Scholar
  10. 10.
    Yao T, Fujimura T, Murayama K, Okumura K, Seko Y (2017) Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in high glucose-induced apoptosis in rat cardiac myocytes and murine pancreatic β-cells. Cells 6:35.  https://doi.org/10.3390/cells6040035 CrossRefGoogle Scholar
  11. 11.
    Wakabayashi Y, Usui Y, Okunuki Y, Kezuka T, Takeuchi M, Goto H, Iwasaki T (2010) Correlation of vascular endothelial growth factor with chemokines in the vitreous in diabetic retinopathy. Retina 30:339–344.  https://doi.org/10.1097/IAE.0b013e3181bd2f44 CrossRefGoogle Scholar
  12. 12.
    Tanaka K, Yao T, Fujimura T, Murayama K, Fukuda S, Okumura K, Seko Y (2016) Marked elevation of plasma levels of oxidative stress-responsive apoptosis inducing protein in dialysis patients. Kidney Int Rep 1:321–324.  https://doi.org/10.1016/j.ekir.2016.08.011 CrossRefGoogle Scholar
  13. 13.
    Yao T, Tanaka K, Fujimura T, Murayama K, Fukuda S, Okumura K, Seko Y (2016) Plasma levels of oxidative stress-responsive apoptosis inducing protein (ORAIP) in patients with atrial fibrillation. Int J Cardiol 222:528–530.  https://doi.org/10.1016/j.ijcard.2016.08.005 CrossRefGoogle Scholar
  14. 14.
    Tanaka K, Yao T, Sato K, Okumura K, Seko Y (2017) Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in the cardiac injury in patients with heart failure. Ann Pharmacol Pharm 2:1100Google Scholar
  15. 15.
    Yao T, Fujimura T, Murayama K, Seko Y (2016) Plasma levels of oxidative stress-responsive apoptosis inducing protein (ORAIP) in rats subjected to physicochemical oxidative stresses. Biosci Rep 36:e00317.  https://doi.org/10.1042/BSR20160044 CrossRefGoogle Scholar
  16. 16.
    Shanab AY, Nakazawa T, Ryu M, Tanaka Y, Himori N, Taguchi K, Yasuda M, Watanabe R, Takano J, Saido T, Minegishi N (2012) Metabolic stress response implicated in diabetic retinopathy: the role of calpain, and the therapeutic impact of calpain inhibitor. Neurobiol Dis 48:556–567.  https://doi.org/10.1016/j.nbd.2012.07.025 CrossRefGoogle Scholar
  17. 17.
    Gupta N, Mansoor S, Sharma A, Sapkal A, Sheth J, Falatoonzadeh P, Kuppermann BD, Kenney MC (2013) Diabetic retinopathy and VEGF. Open Ophthalmol J 7:4–10.  https://doi.org/10.2174/1874364101307010004 CrossRefGoogle Scholar
  18. 18.
    Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG (2012) Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 119:789–801.  https://doi.org/10.1016/j.ophtha.2011.12.039 CrossRefGoogle Scholar
  19. 19.
    Falavarjani KG, Nguyen QD (2013) Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye 27:787–794.  https://doi.org/10.1038/eye.2013.107 CrossRefGoogle Scholar
  20. 20.
    Mandal LK, Choudhuri S, Dutta D, Mitra B, Kundu S, Chowdhury IH, Sen A, Chatterjee M, Bhattacharya B (2013) Oxidative stress-associated neuroretinal dysfunction and nitrosative stress in diabetic retinopathy. Can J Diabetes 37:401–407.  https://doi.org/10.1016/j.jcjd.2013.05.004 CrossRefGoogle Scholar
  21. 21.
    Amato R, Biagioni M, Cammalleri M, Dal Monte M, Casini G (2016) VEGF as a survival factor in ex vivo models of early diabetic retinopathy. Invest Ophthalmol Vis Sci 57:3066–3076.  https://doi.org/10.1167/iovs.16-19285 CrossRefGoogle Scholar
  22. 22.
    Jiang Y, Sang Y, Qiu Q (2017) MicroRNA-383 mediates high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells by repressing peroxiredoxin 3. Am J TrMnsl Res 9:2374–2383Google Scholar
  23. 23.
    Hammes HP (2018) Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia 61:29–38.  https://doi.org/10.1007/s00125-017-4435-8 CrossRefGoogle Scholar
  24. 24.
    Jiao C, Dean Eliott MD, Spee C, He S, Wang K, Mullins RF, Hinton DR, Sohn EH (2017) Apoptosis and angiofibrosis in diabetic tractional membranes after vascular endothelial growth factor inhibition: results of a prospective trial report no. 2. Retina 39:265–273.  https://doi.org/10.1097/IAE.0000000000001952 CrossRefGoogle Scholar
  25. 25.
    Campochiaro PA, Khanani A, Singer M, Patel S, Boyer D, Dugel P, Kherani S, Withers B, Gambino L, Peters K, Brigell M (2016) Enhanced benefit in diabetic macular edema from akb-9778 tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology 123:1722–1730.  https://doi.org/10.1016/j.ophtha.2016.04.025 CrossRefGoogle Scholar
  26. 26.
    Regula JT, von Leithner PL, Foxton R, Barathi VA, Cheung CM, Tun SB, Wey YS, Iwata D, Dostalek M, Moelleken J, Stubenrauch KG (2016) Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med 8:1265–1288.  https://doi.org/10.15252/emmm.201505889 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Ophthalmology, Diabetes CenterTokyo Women’s Medical UniversityTokyoJapan
  2. 2.Division of Cardiovascular Medicine, Institute for Adult DiseasesAsahi Life FoundationTokyoJapan
  3. 3.Department of Biofunctional Microbiota, Graduate School of MedicineJuntendo UniversityTokyoJapan

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