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Role of Microglia in the Retinal Neurodegeneration in Diabetic Rats

Author: ChenXiaoFei
Tutor: ZhangMaoNian
School: PLA Postgraduate Medical School
Course: Ophthalmology
Keywords: Diabetic retinopathy Microglia Neurodegeneration Inflammatory factors Neurotoxicity
CLC: R774.1
Type: PhD thesis
Year: 2012
Downloads: 158
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Abstract


Objectives1. To study characteristics of microglial activation in the retina of STZ-induceddiabetic rats, including cell morphology, cell density and laminar distribution,proportion of activated microglia and Iba-1mRNAexpression in the retina.2. To study whether retinal microglia could be depleted by clodronate liposomes afterintravitreous injection in normal and diabetic rats.3. To study changes in number of retinal ganglion cells, apoptosis of retinal ganglioncells, inner retinal thickness, retinal Iba-1, TNF-α and IL-1β mRNA expression aftermicroglial depletion by clodronate liposomes in normal and diabetic rats.Methods1. In normal rats and4-week,8-week and12-week diabetic rats induced by STZ,OX-42immunohistochemistry in retinal sections was applied to investigate cellmorphology, cell density, laminar distribution in the retina and proportion of activatedmicroglia; retinal Iba-1mRNAexpression was evaluated by Real-time PCR.2. In normal and3-week,4-week and5-week diabetic rats, clodronate liposomes wasintravitreously injected with PBS as control injected in the other eye.1week afterintravitreous injection, OX-42immunohistochemistry in retinal sections and cellcount were applied to evaluate removal efficiency of clodronate liposomes on retinalmicroglia. In3-week diabetic rats,2weeks,3weeks and4weeks respectively afterintravitreous injection of clodronate liposomes and PBS, OX-42immuno-histochemistry in retinal sections and cell count were applied to evaluate effectiveduration of clodronate liposomes.3. In normal and3-week diabetic rats, intravitreous injection of clodronate liposomesand PBS was performed, followed by a repeated injection3weeks later.2weeks after the second injection, depletion of microglia was evaluated by OX-42immuno-histochemistry and Real-time PCR. Number of retinal ganglion cells was measured byNeuN immunohistochemistry and cell count. Apoptosis of ganglion cells was detectedby NeuN/TUNEL double staining in retinal sections. Inner retinal thickness wasmeasured in retinal sections. Retinal TNF-α and IL-1β mRNA expression wasevaluated by Real-time PCR.Results1. In the retina of4-week,8-week and12-week diabetic rats, a portion of microgliashowed ameboid-shaped cell body, or enlarged cell body with shorter, thicker and lessprocesses. Cell density of microglia in the retina was not different among all groups.Microglia were mainly distributed in the nerve fiber layer/ganglion cell layer and theinner plexiform layer of retina in normal and diabetic rats. In12-week diabetic rats,the proportion of microglia located in the nerve fiber layer/ganglion cell layer wasincreased obviously with a concomitant decrease in the inner plexiform layer. In8-week and12-week diabetic rats, distribution of microglia in the optic nerve was lessregular than that in nomal and4-week diabetic rats, with obvious increase in retinalIba-1mRNAexpression.3.5weeks after intravitreous injection of clodronate liposomes, the number of retinalmicroglia decreased obviously with a concomitant decline of Iba-1mRNA levelscompared with contralateral eyes in both normal and diabetic rats. The number ofretinal ganglion cells and inner retinal thickness were reduced obviously in diabeticrats, while the reductions were attenuated significantly in eyes receiving clodronateliposomes. In normal rats, the number of retinal ganglion cells and inner retinalthickness were not changed by clodronate liposomes. Retinal TNF-α mRNAlevel wasincreased in diabetic rats compared with normal controls, while its levels werereduced by clodronate liposomes in both normal and diabetic rats. Retinal IL-1βmRNA level in diabetic rats was not different with that in normal controls, while itslevel was reduced by clodronate liposomes in diabetic rats.Conclusions1. Microglia are activated in the retina of diabetic rats, characterized by changes in cell morphology, laminar distribution in the retina, increase in proportion of activated microglia and retinal Iba-1mRNA expression.2. Clodronate liposomes are effective in depletion of retinal microglia in both normal and diabetic rats after intravitreous injection.3. In diabetic rats, after retinal microglia are depleted by clodronate liposomes, the reduction of retinal ganglion cell number and inner retinal thickness are both attenuated with concomitant decline in retinal TNF-a and IL-1β mRNA expression.4. In the retina of diabetic rats, microglia participate in retinal neurodegeneration with involvement of TNF-a and IL-1β.

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CLC: > Medicine, health > Ophthalmology > Retina and optic nerve diseases > Retinal disease
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