Skip to main content
SpringerLink
Log in

The retinal pigment epithelial response after retinal laser photocoagulation in diabetic mice

  • Original Article
  • Published:
Lasers in Medical Science Aims and scope Submit manuscript

Abstract

To investigate the characteristics of regenerated retinal pigment epithelial (RPE) cells after retinal laser photocoagulation in diabetic mice. C57BL/6J mice were used to induce diabetes using intraperitoneal injection of streptozotocin. The proliferation of RPE cells after laser photocoagulation was determined using the 5-ethynyl-2′-deoxyuridine (EdU) assay in both diabetic and wild-type mice. The morphological changes of RPE cells were evaluated by using Voronoi diagram from immunostaining for ß-catenin. Characteristics of regenerated cells were evaluated by quantifying the mRNA and protein levels of RPE and epithelial-mesenchymal transition (EMT) markers. There were significantly less EdU-positive cells in laser-treated areas in diabetic mice than wild-type mice. Hexagonality was extensively lost in diabetic mice. Many EdU-positive cells were co-localized with Otx2-positive cells in the center of the laser-treated areas in wild-type mice, but only EdU-positive cells were widely distributed in diabetic mice. Quantitative analysis of mRNA and protein levels showed that the expression levels of RPE markers, Pax6, Mitf, and Otx2, were significantly decreased in RPE of diabetic mice compared with that of wild-type mice, whereas the expression levels of EMT markers, vimentin and fibronectin, were significantly increased. The proliferation and hexagonality of regenerating RPE cells were impaired after laser photocoagulation, and the regenerated RPE cells lost their original properties in diabetic mice. Further clinical research is needed to elucidate the RPE response after laser photocoagulation in diabetic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Prokofyeva E, Zrenner E (2012) Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 47:171–188

    Article  PubMed  Google Scholar 

  2. Preliminary report on effects of photocoagulation therapy (1976) The diabetic retinopathy study research group. Am J Ophthalmol 81:383–396

    Article  Google Scholar 

  3. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings (1978). Ophthalmology 85:82–106

  4. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8 (1981) The diabetic retinopathy study research group. Ophthalmology 88:583–600

    Article  Google Scholar 

  5. Regnier S, Malcolm W, Allen F, Wright J, Bezlyak V (2014) Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis. PLoS One 9:e102309

    Article  PubMed  PubMed Central  Google Scholar 

  6. Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK (2010) Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117:1064–1077.e1035

    Article  PubMed  Google Scholar 

  7. Frisch GD, Shawaluk PD, Adams DO (1974) Remote nerve fibre bundle alterations in the retina as caused by argon laser photocoagulation. Nature 248:433–435

    Article  CAS  PubMed  Google Scholar 

  8. Watzke RC, Soldevilla JD, Trune DR (1993) Morphometric analysis of human retinal pigment epithelium: correlation with age and location. Curr Eye Res 12:133–142

    Article  CAS  PubMed  Google Scholar 

  9. Marshall J (1970) Thermal and mechanical mechanisms in laser damage to the retina. Investig Ophthalmol 9:97–115

    CAS  Google Scholar 

  10. Tababat-Khani P, Berglund LM, Agardh CD, Gomez MF, Agardh E (2013) Photocoagulation of human retinal pigment epithelial cells in vitro: evaluation of necrosis, apoptosis, cell migration, cell proliferation and expression of tissue repairing and cytoprotective genes. PLoS One 8:e70465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pollack A, Korte GE (1990) Repair of retinal pigment epithelium and its relationship with capillary endothelium after krypton laser photocoagulation. Invest Ophthalmol Vis Sci 31:890–898

    CAS  PubMed  Google Scholar 

  12. Romero-Aroca P, Reyes-Torres J, Baget-Bernaldiz M, Blasco-Sune C (2014) Laser treatment for diabetic macular edema in the 21st century. Curr Diabetes Rev 10:100–112

    Article  PubMed  PubMed Central  Google Scholar 

  13. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881

    Article  CAS  PubMed  Google Scholar 

  14. Lee SH, Kim HD, Park YJ, Ohn YH, Park TK (2015) Time-dependent changes of cell proliferation after laser photocoagulation in mouse chorioretinal tissue. Invest Ophthalmol Vis Sci 56:2696–2708

    Article  CAS  PubMed  Google Scholar 

  15. Han JW, Lyu J, Park YJ, Jang SY, Park TK (2015) Wnt/beta-catenin signaling mediates regeneration of retinal pigment epithelium after laser photocoagulation in mouse eye. Invest Ophthalmol Vis Sci 56:8314–8324

    Article  CAS  PubMed  Google Scholar 

  16. Kim HD, Jang SY, Lee SH, Kim YS, Ohn YH, Brinkmann R, Park TK (2016) Retinal pigment epithelium responses to selective retina therapy in mouse eyes. Invest Ophthalmol Vis Sci 57:3486–3495

    Article  CAS  PubMed  Google Scholar 

  17. Rangarajan A, Weinberg RA (2003) Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959

    Article  CAS  PubMed  Google Scholar 

  18. Demetrius L (2005) Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans. EMBO Rep 6 Spec No:S39–S44

    Article  CAS  PubMed  Google Scholar 

  19. Maeshima K, Utsugi-Sutoh N, Otani T, Kishi S (2004) Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina 24:507–511

    Article  PubMed  Google Scholar 

  20. Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, Wu M, Boulton M, Lyons TJ, Gao G, Ma JX (2009) Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am J Pathol 175:2676–2685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang SJ, Li YF, Tan RR, Tsoi B, Huang WS, Huang YH, Tang XL, Hu D, Yao N, Yang X, Kurihara H, Wang Q, He RR (2016) A new gestational diabetes mellitus model: hyperglycemia-induced eye malformation via inhibition of Pax6 in the chick embryo. Dis Model Mech 9:177–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Villarroel M, Garcia-Ramirez M, Corraliza L, Hernandez C, Simo R (2009) Effects of high glucose concentration on the barrier function and the expression of tight junction proteins in human retinal pigment epithelial cells. Exp Eye Res 89:913–920

    Article  CAS  PubMed  Google Scholar 

  23. von Leithner PL, Ciurtin C, Jeffery G (2010) Microscopic mammalian retinal pigment epithelium lesions induce widespread proliferation with differences in magnitude between center and periphery. Mol Vis 16:570–581

    Google Scholar 

  24. Kasaoka M, Ma J, Lashkari K (2012) c-Met modulates RPE migratory response to laser-induced retinal injury. PLoS One 7:e40771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jain A, Blumenkranz MS, Paulus Y, Wiltberger MW, Andersen DE, Huie P, Palanker D (2008) Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol 126:78–85

    Article  PubMed  Google Scholar 

  26. Brem H, Tomic-Canic M (2007) Cellular and molecular basis of wound healing in diabetes. J Clin Invest 117:1219–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alnek K, Kisand K, Heilman K, Peet A, Varik K, Uibo R (2015) Increased blood levels of growth factors, proinflammatory cytokines, and Th17 cytokines in patients with newly diagnosed type 1 diabetes. PLoS One 10:e0142976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Busik JV, Mohr S, Grant MB (2008) Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes 57:1952–1965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, Merchant A, Galiano RD, Tomic-Canic M (2005) Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol 167:59–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Raviv S, Bharti K, Rencus-Lazar S, Cohen-Tayar Y, Schyr R, Evantal N, Meshorer E, Zilberberg A, Idelson M, Reubinoff B, Grebe R, Rosin-Arbesfeld R, Lauderdale J, Lutty G, Arnheiter H, Ashery-Padan R (2014) PAX6 regulates melanogenesis in the retinal pigmented epithelium through feed-forward regulatory interactions with MITF. PLoS Genet 10:e1004360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ma X, Pan L, Jin X, Dai X, Li H, Wen B, Chen Y, Ma A, Qu J, Hou L (2012) Microphthalmia-associated transcription factor acts through PEDF to regulate RPE cell migration. Exp Cell Res 318:251–261

    Article  CAS  PubMed  Google Scholar 

  32. Torero Ibad R, Rheey J, Mrejen S, Forster V, Picaud S, Prochiantz A, Moya KL (2011) Otx2 promotes the survival of damaged adult retinal ganglion cells and protects against excitotoxic loss of visual acuity in vivo. J Neurosci 31:5495–5503

    Article  CAS  PubMed  Google Scholar 

  33. Housset M, Samuel A, Ettaiche M, Bemelmans A, Beby F, Billon N, Lamonerie T (2013) Loss of Otx2 in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration. J Neurosci 33:9890–9904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tamiya S, Liu L, Kaplan HJ (2010) Epithelial-mesenchymal transition and proliferation of retinal pigment epithelial cells initiated upon loss of cell-cell contact. Invest Ophthalmol Vis Sci 51:2755–2763

    Article  PubMed  Google Scholar 

  35. Scoles D, Sulai YN, Dubra A (2013) In vivo dark-field imaging of the retinal pigment epithelium cell mosaic. Biomed Opt Express 4:1710–1723

    Article  PubMed  PubMed Central  Google Scholar 

  36. Burns SA, Elsner AE, Sapoznik KA, Warner RL, Gast TJ (2018) Adaptive optics imaging of the human retina. Prog Retin Eye Res

  37. Datta R, Alfonso-Garcia A, Cinco R, Gratton E (2015) Fluorescence lifetime imaging of endogenous biomarker of oxidative stress. Sci Rep 5:9848

    Article  PubMed  PubMed Central  Google Scholar 

  38. Dysli C, Wolf S, Berezin MY, Sauer L, Hammer M, Zinkernagel MS (2017) Fluorescence lifetime imaging ophthalmoscopy. Prog Retin Eye Res 60:120–143

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) (No. 2016R1A2B4008376; Seoul, Republic of Korea). This work was partially supported by the Soonchunhyang University Research Fund. The funding organization had no role in the design or conducted of this research.

Author information

Author notes

  1. Sun Young Jang and In Hwan Cho contributed equally to the work presented here and should therefore be regarded as equivalent first authors.

  2. Tae Kwann Park and Jungmook Lyu should be regarded as equivalent corresponding authors.

Authors and Affiliations

  1. Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, #170 Jomaru-ro, Bucheon-si, Gyeonggi-do, 14584, South Korea

    Sun Young Jang, Sang Earn Woo & Tae Kwann Park

  2. Department of Ophthalmology, College of Medicine, Soonchunhyang University, Cheonan-si, Chungcheongnam-do, South Korea

    Sun Young Jang, In Hwan Cho & Tae Kwann Park

  3. Department of Ophthalmology, Soonchunhyang University Hospital Cheonan, Cheonan-si, Chungcheongnam-do, South Korea

    In Hwan Cho

  4. Research center for clinical medicine, Soonchunhyang University Hospital Bucheon, Bucheon-si, Gyeonggi-do, South Korea

    Jin Young Yang, Ha Yan Park, Sanjar Batirovich Madrakhimov, Hun Soo Chang & Tae Kwann Park

  5. Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Bucheon-si, Gyeonggi-do, South Korea

    Jin Young Yang, Hun Soo Chang & Tae Kwann Park

  6. Department of Medical Science, Konyang University, 685 Gasoowon-dong, Seo-gu, Daejeon 302-718, Daejeon, South Korea

    Jungmook Lyu

Authors
  1. Sun Young Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. In Hwan Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Young Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ha Yan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sang Earn Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sanjar Batirovich Madrakhimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hun Soo Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jungmook Lyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tae Kwann Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jungmook Lyu or Tae Kwann Park.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The Animal Care Committee of Soonchunhyang University Bucheon Hospital.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jang, S.Y., Cho, I.H., Yang, J.Y. et al. The retinal pigment epithelial response after retinal laser photocoagulation in diabetic mice. Lasers Med Sci 34, 179–190 (2019). https://doi.org/10.1007/s10103-018-2680-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10103-018-2680-9

Keywords

Search

Navigation