Skip to main content
Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology 4/2015

01.04.2015 | Retinal Disorders

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

verfasst von: Xiaofei Chen, Huanfen Zhou, Yan Gong, Shihui Wei, Maonian Zhang

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Moss S, Klein R, Klein B (1998) The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105:998–1003CrossRefPubMed Moss S, Klein R, Klein B (1998) The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105:998–1003CrossRefPubMed
2.
Zurück zum Zitat Bunce C, Xing W, Wormald R (2010) Causes of blind and partial sight certifications in England and Wales: April 2007-March 2008. Eye (Lond) 24:1692–1699CrossRef Bunce C, Xing W, Wormald R (2010) Causes of blind and partial sight certifications in England and Wales: April 2007-March 2008. Eye (Lond) 24:1692–1699CrossRef
3.
Zurück zum Zitat Gardner T, Antonetti D, Barber A, LaNoue K, Levison S (2002) Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 47(Suppl 2):S253–S262CrossRefPubMed Gardner T, Antonetti D, Barber A, LaNoue K, Levison S (2002) Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 47(Suppl 2):S253–S262CrossRefPubMed
4.
Zurück zum Zitat Fletcher E, Phipps J, Wilkinson-Berka J (2005) Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 88:132–145CrossRefPubMed Fletcher E, Phipps J, Wilkinson-Berka J (2005) Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 88:132–145CrossRefPubMed
5.
Zurück zum Zitat Kern T (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103CrossRefPubMedCentralPubMed Kern T (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103CrossRefPubMedCentralPubMed
6.
Zurück zum Zitat Kim Y, Joh T (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347CrossRefPubMed Kim Y, Joh T (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347CrossRefPubMed
7.
Zurück zum Zitat Zeng H, Green WR, Tso MOM (2008) Microglial activation in human diabetic retinopathy. Arch Ophthalmol 126:227–232CrossRefPubMed Zeng H, Green WR, Tso MOM (2008) Microglial activation in human diabetic retinopathy. Arch Ophthalmol 126:227–232CrossRefPubMed
8.
Zurück zum Zitat Rungger–Brändle E, Dosso AA, Leuenberger PM (2000) Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1971–1980PubMed Rungger–Brändle E, Dosso AA, Leuenberger PM (2000) Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1971–1980PubMed
9.
Zurück zum Zitat 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 47:612–623CrossRefPubMed 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 47:612–623CrossRefPubMed
10.
Zurück zum Zitat Zeng X, Y-k NG, E-a L (2000) Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci 11:463–471CrossRef Zeng X, Y-k NG, E-a L (2000) Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci 11:463–471CrossRef
11.
Zurück zum Zitat 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 128:215–224CrossRefPubMed 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 128:215–224CrossRefPubMed
12.
Zurück zum Zitat Sandhir R, Onyszchuk G, Berman N (2008) Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp Neurol 213:372–380CrossRefPubMedCentralPubMed Sandhir R, Onyszchuk G, Berman N (2008) Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp Neurol 213:372–380CrossRefPubMedCentralPubMed
13.
Zurück zum Zitat 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 57:239–247PubMedCentralPubMed 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 57:239–247PubMedCentralPubMed
14.
Zurück zum Zitat Davis E, Foster T, Thomas W (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73–78CrossRefPubMed Davis E, Foster T, Thomas W (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73–78CrossRefPubMed
15.
Zurück zum Zitat 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 31:57–71CrossRefPubMed 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 31:57–71CrossRefPubMed
16.
Zurück zum Zitat Hanisch U, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefPubMed Hanisch U, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefPubMed
17.
Zurück zum Zitat Streit W (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139CrossRefPubMed Streit W (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139CrossRefPubMed
18.
Zurück zum Zitat 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 54:1559–1565CrossRefPubMed 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 54:1559–1565CrossRefPubMed
19.
Zurück zum Zitat 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 34:928–938CrossRefPubMed 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 34:928–938CrossRefPubMed
20.
Zurück zum Zitat 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 89:513–517CrossRefPubMedCentralPubMed 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 89:513–517CrossRefPubMedCentralPubMed
21.
Zurück zum Zitat 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 40:2275–2282PubMed 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 40:2275–2282PubMed
22.
Zurück zum Zitat Ohsawa K, Kohsaka S (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia 59:1793–1799CrossRefPubMed Ohsawa K, Kohsaka S (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia 59:1793–1799CrossRefPubMed
23.
Zurück zum Zitat 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 60:1122–1133CrossRefPubMedCentralPubMed 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 60:1122–1133CrossRefPubMedCentralPubMed
24.
25.
Zurück zum Zitat 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 46:2992–2999CrossRefPubMed 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 46:2992–2999CrossRefPubMed
26.
Zurück zum Zitat Kowluru R, Odenbach S (2004) Role of interleukin-1beta in the development of retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci 45:4161–4166CrossRefPubMed Kowluru R, Odenbach S (2004) Role of interleukin-1beta in the development of retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci 45:4161–4166CrossRefPubMed
27.
Zurück zum Zitat 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) 20:1366–1369CrossRef 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) 20:1366–1369CrossRef
28.
Zurück zum Zitat 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 47:1448–1457CrossRefPubMed 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 47:1448–1457CrossRefPubMed
29.
Zurück zum Zitat 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 49:3605–3610CrossRefPubMed 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 49:3605–3610CrossRefPubMed
30.
Zurück zum Zitat 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 90:89–101CrossRefPubMed 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 90:89–101CrossRefPubMed
31.
Zurück zum Zitat 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 373:159–164CrossRef 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 373:159–164CrossRef
32.
Zurück zum Zitat 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 27:7751–7761CrossRefPubMed 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 27:7751–7761CrossRefPubMed
33.
Zurück zum Zitat Wang A, Yu A, Lau L, Lee C, Wu M, Zhu X, Tso M (2005) Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47:152–158CrossRefPubMed Wang A, Yu A, Lau L, Lee C, Wu M, Zhu X, Tso M (2005) Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47:152–158CrossRefPubMed
34.
Zurück zum Zitat 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 6:797–801CrossRefPubMed 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 6:797–801CrossRefPubMed
35.
Zurück zum Zitat 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 279:19948–19954CrossRefPubMed 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 279:19948–19954CrossRefPubMed
Metadaten
Titel
Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes
verfasst von
Xiaofei Chen
Huanfen Zhou
Yan Gong
Shihui Wei
Maonian Zhang
Publikationsdatum
01.04.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 4/2015
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-014-2727-y

Weitere Artikel der Ausgabe 4/2015

Graefe's Archive for Clinical and Experimental Ophthalmology 4/2015 Zur Ausgabe

Neu im Fachgebiet Augenheilkunde

Ophthalmika in der Schwangerschaft

Die Verwendung von Ophthalmika in der Schwangerschaft und Stillzeit stellt immer eine Off-label-Anwendung dar. Ein Einsatz von Arzneimitteln muss daher besonders sorgfältig auf sein Risiko-Nutzen-Verhältnis bewertet werden. In der vorliegenden …

Operative Therapie und Keimnachweis bei endogener Endophthalmitis

Vitrektomie Originalie

Die endogene Endophthalmitis ist eine hämatogen fortgeleitete, bakterielle oder fungale Infektion, die über choroidale oder retinale Gefäße in den Augapfel eingeschwemmt wird [ 1 – 3 ]. Von dort infiltrieren die Keime in die Netzhaut, den …

Bakterielle endogene Endophthalmitis

Vitrektomie Leitthema

Eine endogene Endophthalmitis stellt einen ophthalmologischen Notfall dar, der umgehender Diagnostik und Therapie bedarf. Es sollte mit geeigneten Methoden, wie beispielsweise dem Freiburger Endophthalmitis-Set, ein Keimnachweis erfolgen. Bei der …

So erreichen Sie eine bestmögliche Wundheilung der Kornea

Die bestmögliche Wundheilung der Kornea, insbesondere ohne die Ausbildung von lichtstreuenden Narben, ist oberstes Gebot, um einer dauerhaften Schädigung der Hornhaut frühzeitig entgegenzuwirken und die Funktion des Auges zu erhalten.   

Update Augenheilkunde

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.