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M ü ller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes

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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.

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Expression of survival and trophic factors in the retina of conditional Vegfr2 KO mice (n ≥ 6). Loss of VEGFR2 in Müller cells significantly exacerbated the reduction of pAKT (A) 4 months after STZ injection and GDNF (B) and BDNF (C) 10 months after the onset of diabetes in the retina of conditional Vegfr2 KO mice. tAKT, total AKT. Error bar: SD. Ctrl, control; ns, not significant. **P < 0.01.
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Figure 6: Expression of survival and trophic factors in the retina of conditional Vegfr2 KO mice (n ≥ 6). Loss of VEGFR2 in Müller cells significantly exacerbated the reduction of pAKT (A) 4 months after STZ injection and GDNF (B) and BDNF (C) 10 months after the onset of diabetes in the retina of conditional Vegfr2 KO mice. tAKT, total AKT. Error bar: SD. Ctrl, control; ns, not significant. **P < 0.01.

Mentions: To determine the neuroprotective mechanism(s) of VEGFR2-mediated signaling in Müller glia in DR, we examined the degree of apoptosis in the retinas of conditional Vegfr2 KO mice. Under normal conditions, there was no significant alteration in the number of apoptotic cells in the retina between conditional Vegfr2 KO mice and controls (Fig. 5). However, loss of VEGFR2-mediated signaling in Müller cells significantly elevated diabetes-induced neuronal apoptosis 4 months after the STZ injection (Fig. 5). In addition, the level of activated cellular survival signal, pAKT, was only 44.3% of that of controls in the conditional Vegfr2 KO mice at 4 months after the onset of diabetes (Fig. 6A), which was less than 25% of that under normal conditions. These data suggest that the retinal neuronal loss in diabetic conditional Vegfr2 KO mice was likely a consequence of accelerated reduction of pAKT survival signals in retinal neurons, which triggered apoptosis and caused elevated retinal degeneration.


M ü ller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes
Expression of survival and trophic factors in the retina of conditional Vegfr2 KO mice (n ≥ 6). Loss of VEGFR2 in Müller cells significantly exacerbated the reduction of pAKT (A) 4 months after STZ injection and GDNF (B) and BDNF (C) 10 months after the onset of diabetes in the retina of conditional Vegfr2 KO mice. tAKT, total AKT. Error bar: SD. Ctrl, control; ns, not significant. **P < 0.01.
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Related In: Results  -  Collection

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Figure 6: Expression of survival and trophic factors in the retina of conditional Vegfr2 KO mice (n ≥ 6). Loss of VEGFR2 in Müller cells significantly exacerbated the reduction of pAKT (A) 4 months after STZ injection and GDNF (B) and BDNF (C) 10 months after the onset of diabetes in the retina of conditional Vegfr2 KO mice. tAKT, total AKT. Error bar: SD. Ctrl, control; ns, not significant. **P < 0.01.
Mentions: To determine the neuroprotective mechanism(s) of VEGFR2-mediated signaling in Müller glia in DR, we examined the degree of apoptosis in the retinas of conditional Vegfr2 KO mice. Under normal conditions, there was no significant alteration in the number of apoptotic cells in the retina between conditional Vegfr2 KO mice and controls (Fig. 5). However, loss of VEGFR2-mediated signaling in Müller cells significantly elevated diabetes-induced neuronal apoptosis 4 months after the STZ injection (Fig. 5). In addition, the level of activated cellular survival signal, pAKT, was only 44.3% of that of controls in the conditional Vegfr2 KO mice at 4 months after the onset of diabetes (Fig. 6A), which was less than 25% of that under normal conditions. These data suggest that the retinal neuronal loss in diabetic conditional Vegfr2 KO mice was likely a consequence of accelerated reduction of pAKT survival signals in retinal neurons, which triggered apoptosis and caused elevated retinal degeneration.

View Article: PubMed Central - PubMed

ABSTRACT

To dissect the role of vascular endothelial growth factor receptor-2 (VEGFR2) in M&uuml;ller cells and its effect on neuroprotection in diabetic retinopathy (DR), we disrupted VEGFR2 in mouse M&uuml;ller glia and determined its effect on M&uuml;ller cell survival, neuronal integrity, and trophic factor production in diabetic retinas. Diabetes was induced with streptozotocin. Retinal function was measured with electroretinography. M&uuml;ller cell and neuronal densities were assessed with morphometric and immunohistochemical analyses. Loss of VEGFR2 caused a gradual reduction in M&uuml;ller 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&ndash;derived neurotrophic factor and brain-derived neurotrophic factor. Our results suggest that VEGFR2-mediated M&uuml;ller 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 M&uuml;ller cell ablation, which will be useful for exploring the cellular mechanisms of neuronal alteration in DR.

No MeSH data available.


Related in: MedlinePlus