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Müller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes
Shuhua Fu1, Shuqian Dong2, Meili Zhu3
1Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, China Section of Endocrinology and Diabetes, Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Abstract:
To dissect the role of vascular endothelial growth factor receptor-2 (VEGFR2) in Müller cells and its effect on neuroprotection in diabetic retinopathy (DR), we disrupted VEGFR2 in mouse Müller glia and determined its effect on Müller cell survival, neuronal integrity, and trophic factor production in diabetic retinas. Diabetes was induced with streptozotocin. Retinal function was measured with electroretinography. Müller cell and neuronal densities were assessed with morphometric and immunohistochemical analyses. Loss of VEGFR2 caused a gradual reduction in Müller glial density, which reached to a significant level 10 months after the onset of diabetes. This observation was accompanied by an age-dependent decrease of scotopic and photopic electroretinography amplitudes and accelerated loss of rod and cone photoreceptors, ganglion cell layer cells, and inner nuclear layer neurons and by a significant reduction of retinal glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Our results suggest that VEGFR2-mediated Müller cell survival is required for the viability of retinal neurons in diabetes. The genetically altered mice established in this study can be used as a diabetic animal model of nontoxin-induced Müller cell ablation, which will be useful for exploring the cellular mechanisms of neuronal alteration in DR.
Insights
Vascular endothelial growth factor receptor-2 (VEGFR2) is crucial for Müller cell survival, protecting retinal neurons in diabetic retinopathy. Loss of VEGFR2 accelerates neuronal damage and vision loss in diabetic mice.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- Diabetic retinopathy (DR) involves complex cellular changes in the retina.
- Müller cells play a critical role in retinal homeostasis and neuroprotection.
- The specific function of VEGFR2 within Müller cells in DR remains incompletely understood.
Purpose of the Study:
- To investigate the role of vascular endothelial growth factor receptor-2 (VEGFR2) in Müller cells.
- To determine the impact of VEGFR2 disruption in Müller glia on neuroprotection in a mouse model of diabetic retinopathy.
Main Methods:
- Disruption of VEGFR2 specifically in mouse Müller glia.
- Induction of diabetes using streptozotocin.
- Assessment of retinal function via electroretinography.
- Morphometric and immunohistochemical analyses of Müller cell and neuronal densities.
- Quantification of neurotrophic factors.
Main Results:
- Loss of VEGFR2 in Müller cells led to a significant reduction in Müller glial density 10 months post-diabetes onset.
- This was associated with age-dependent decreases in electroretinography amplitudes.
- Accelerated loss of photoreceptors, ganglion cells, and inner nuclear layer neurons was observed.
- Significant reduction in glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor levels.
Conclusions:
- VEGFR2 signaling in Müller cells is essential for maintaining Müller cell survival during diabetes.
- VEGFR2-mediated Müller cell survival is critical for the viability of retinal neurons in the context of diabetic retinopathy.
- This study establishes a novel mouse model for studying non-toxin-induced Müller cell ablation in DR.
