Skip to main content

Advertisement

Log in

Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes

  • Retinal Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

Microglial activation has been recognized as a neuropathological feature in diabetic retinopathy. But the early spatiotemporal characterization of microglial activation in the retina and the optic nerve of diabetic animals has not been fully investigated. The purpose of this study was to investigate early sequential changes of microglia in the retinas of rats with streptozotocin-induced diabetes. Microglia in the optic nerves of rats with streptozotocin-induced diabetes were also studied.

Methods

In 4-week, 8-week, and 12-week diabetic and normal control rats, microglial activation in the retinas and optic nerves was evaluated by immunolabeling with OX-42 antibody. Density, proportion of activation, and laminar distribution of retinal microglia were quantified. The retinal mRNA level of Iba-1, a microglial-specific marker, was measured by real-time PCR.

Results

The density of retinal microglia was not different between diabetic and control rats, but the proportion of activated microglia increased significantly in diabetic rats at each time point. The proportion of microglia increased obviously in the nerve fiber layer and the ganglion cell layer while decreasing in the inner plexiform layer in 12-week diabetic rats. Moreover, retinal Iba-1 mRNA expression increased in 8-week and 12-week diabetic rats. Processes of microglia in the optic nerves of control rats were aligned with the long axis of nerve fibers, while the alignment was disturbed in diabetic rats.

Conclusions

Morphology, proportion of activation, distribution, and mRNA expression of retinal microglia changed characteristically with the progression of the disease in early-stage diabetic rats.

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

Access this article

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

Similar content being viewed by others

References

  1. Moss S, Klein R, Klein B (1998) The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105:998–1003

    Article  CAS  PubMed  Google Scholar 

  2. Bunce C, Xing W, Wormald R (2010) Causes of blind and partial sight certifications in England and Wales: April 2007-March 2008. Eye (Lond) 24:1692–1699

    Article  CAS  Google Scholar 

  3. Gardner T, Antonetti D, Barber A, LaNoue K, Levison S (2002) Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 47(Suppl 2):S253–S262

    Article  PubMed  Google Scholar 

  4. Fletcher E, Phipps J, Wilkinson-Berka J (2005) Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 88:132–145

    Article  PubMed  Google Scholar 

  5. Kern T (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103

    Article  PubMed Central  PubMed  Google Scholar 

  6. Kim Y, Joh T (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347

    Article  CAS  PubMed  Google Scholar 

  7. Zeng H, Green WR, Tso MOM (2008) Microglial activation in human diabetic retinopathy. Arch Ophthalmol 126:227–232

    Article  PubMed  Google Scholar 

  8. Rungger–Brändle E, Dosso AA, Leuenberger PM (2000) Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1971–1980

    PubMed  Google Scholar 

  9. Gaucher D, Chiappore J-A, Pâques M, Simonutti M, Boitard C, Sahel J, Massin P, Picaud S (2007) Microglial changes occur without neural cell death in diabetic retinopathy. Vis Res 47:612–623

    Article  PubMed  Google Scholar 

  10. Zeng X, Y-k NG, E-a L (2000) Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci 11:463–471

    Article  Google Scholar 

  11. Moss A, Beggs S, Vega-Avelaira D, Costigan M, Hathway G, Salter M, Fitzgerald M (2007) Spinal microglia and neuropathic pain in young rats. Pain 128:215–224

    Article  CAS  PubMed  Google Scholar 

  12. Sandhir R, Onyszchuk G, Berman N (2008) Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp Neurol 213:372–380

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Robinson A, White T, Mason D (1986) Macrophage heterogeneity in the rat as delineated by two monoclonal antibodies MRC OX-41 and MRS OX-42, the latter recognising complement receptor type 3. Immunology 57:239–247

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Davis E, Foster T, Thomas W (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73–78

    Article  CAS  PubMed  Google Scholar 

  15. Raibon E, Sauvé Y, Carter D, Gaillard F (2002) Microglial changes accompanying the promotion of retinal ganglion cell axonal regeneration into peripheral nerve grafts. J Neurocytol 31:57–71

    Article  CAS  PubMed  Google Scholar 

  16. Hanisch U, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  17. Streit W (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  18. Krady J, Basu A, Allen C, Xu Y, LaNoue K, Gardner T, Levison S (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54:1559–1565

    Article  CAS  PubMed  Google Scholar 

  19. Arnal E, Miranda M, Johnsen-Soriano S, Alvarez-Nölting R, Díaz-Llopis M, Araiz J, Cervera E, Bosch-Morell F, Romero FJ (2009) Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Curr Eye Res 34:928–938

    Article  CAS  PubMed  Google Scholar 

  20. Qiao H, Hisatomi T, Sonoda K, Kura S, Sassa Y, Kinoshita S, Nakamura T, Sakamoto T, Ishibashi T (2005) The characterisation of hyalocytes: the origin, phenotype, and turnover. Br J Ophthalmol 89:513–517

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Marie O, Thillaye-Goldenberg B, Naud M, de Kozak Y (1999) Inhibition of endotoxin-induced Uveitis and potentiation of local TNF-a and interleukin-6 mRNA expression by interleukin-13. Invest Ophthalmol Vis Sci 40:2275–2282

    CAS  PubMed  Google Scholar 

  22. Ohsawa K, Kohsaka S (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia 59:1793–1799

    Article  PubMed  Google Scholar 

  23. Ibrahim A, El-Remessy A, Matragoon S, Zhang W, Patel Y, Khan S, Al-Gayyar M, El-Shishtawy M, Liou G (2011) Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. Diabetes 60:1122–1133

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Hanisch U (2002) Microglia as a source and target of cytokines. Glia 40:140–155

    Article  PubMed  Google Scholar 

  25. Zeng H, Zhu X, Zhang C, Yang L, Wu L, Tso M (2005) Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice. Invest Ophthalmol Vis Sci 46:2992–2999

    Article  PubMed  Google Scholar 

  26. Kowluru R, Odenbach S (2004) Role of interleukin-1beta in the development of retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci 45:4161–4166

    Article  PubMed  Google Scholar 

  27. Demircan N, Safran B, Soylu M, Ozcan A, Sizmaz S (2006) Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond) 20:1366–1369

    Article  CAS  Google Scholar 

  28. Kitaoka Y, Kitaoka Y, Kwong J, Ross-Cisneros F, Wang J, Tsai R, Sadun A, Lam T (2006) TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65. Invest Ophthalmol Vis Sci 47:1448–1457

    Article  PubMed  Google Scholar 

  29. Berger S, Savitz S, Nijhawan S, Singh M, David J, Rosenbaum P, Rosenbaum D (2008) Deleterious role of TNF-alpha in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 49:3605–3610

    Article  PubMed  Google Scholar 

  30. Morgan S, Taylor D, Pocock J (2004) Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. J Neurochem 90:89–101

    Article  CAS  PubMed  Google Scholar 

  31. YZ L, CH L, FC C, CM H (2005) Molecular mechanisms responsible for microglia-derived protection of Sprague–Dawley rat brain cells during in vitro ischemia. Neurosci Lett 373:159–164

    Article  Google Scholar 

  32. Yune T, Lee J, Jung G, Kim S, Jiang M, Kim Y, Oh Y, Markelonis G, Oh T (2007) Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci 27:7751–7761

    Article  CAS  PubMed  Google Scholar 

  33. Wang A, Yu A, Lau L, Lee C, Wu M, Zhu X, Tso M (2005) Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47:152–158

    Article  CAS  PubMed  Google Scholar 

  34. Chen M, Ona V, Li M, Ferrante R, Fink K, Zhu S, Bian J, Guo L, Farrell L, Hersch S, Hobbs W, Vonsattel J, Cha J, Friedlander R (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801

    Article  CAS  PubMed  Google Scholar 

  35. Wang J, Wei Q, Wang C, Hill W, Hess D, Dong Z (2004) Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem 279:19948–19954

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maonian Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Zhou, H., Gong, Y. et al. Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes. Graefes Arch Clin Exp Ophthalmol 253, 519–525 (2015). https://doi.org/10.1007/s00417-014-2727-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-014-2727-y

Keywords

Navigation