Abstract
Purpose :
Diabetic retinopathy (DR), a leading cause of blindness, is traditionally regarded as a retinal vascular disorder. However, it is becoming increasingly clear that alteration and degeneration of retinal neurons occur before the onset of microvascular abnormalities in patients and experimental animals of diabetes. To investigate the role of major retinal supporting cells, Müller glia, in neuroprotection in DR, we generated a diabetes-induced Müller cell ablation model by genetic disruption of vascular endothelial growth factor receptor-2 (VEGFR2), and investigated the effect of Müller cell loss on trophic factor production and neuroprotection in diabetic mice.
Methods :
The mouse model was generated by disruption VEGFR2 in Müller glia. The diabetes-induced Müller cell ablation was achieved by inducing diabetes in conditional VEGFR2 knockout mice. Retinal function was measured with electroretinography (ERG). Retinal morphology was assessed in hematoxylin & eosin (H&E) stained sections. The density of Müller cells and cone photoreceptors was evaluated with immunohistochemistry. Gene expression was analyzed with immunoblotting.
Results :
While there was no apparent alteration in retinal morphology, cell density, function, and trophic factor production in Müller cell-specific VEGFR2 knockout mice under normal conditions, the diabetic conditional VEGFR2 knockout mice exhibited a significant loss of glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), major Müller cell-derived neurotrophins. This observation coincided with an age-dependent loss of neuronal density in all retinal layers. Mechanistic investigation also suggests that VEGF signaling in Müller glia may have a direct role in promoting GDNF and BDNF production.
Conclusions :
Among a number of tested trophic factors, only GDNF and BDNF were significantly downregulated in diabetic retinas of conditional VEGFR2 knockout mice. Therefore, GDNF and BDNF may be major neuro-protectants in DR. Additionally, Müller glia may be more vulnerable in diabetes but play more-prominent role in neuroprotection in DR. Finally, VEGF signaling mediated Müller glial survival may be critical to neuroprotection in DR.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.