IHEM   20887
INSTITUTO DE HISTOLOGIA Y EMBRIOLOGIA DE MENDOZA DR. MARIO H. BURGOS
Unidad Ejecutora - UE
artículos
Título:
Effect of autophagy modulators on vascular, glial and neuronal alterations in the oxygen-induced retinopathy mouse model
Autor/es:
PAZ MC; FADER KAISER C; RIDANO MAGALI E; CHIABRANDO GA; SUBIRADA CALDARONE PAULA; LORENC VE; SANCHEZ MC
Revista:
Frontiers in Cellular Neuroscience
Editorial:
Frontiers Media S.A.
Referencias:
Año: 2019 vol. 13 p. 1 - 18
ISSN:
1662-5102
Resumen:
Hypoxia is one of the main insults in proliferative retinopathies, leading to neovascularization and neurodegeneration. To maintain homeostasis neurons, require efficient degradation and recycling systems. Autophagy participates in retinal cell death, but it is also a cell survival mechanism. Here, we analysed the role of autophagy at the three characteristics time periods in the oxygen-induced retinopathy (OIR) mouse model and determining if its modulation can improve vascular and non-vascular alterations. Postnatal day (P)17 OIR mouse retinas showed a significant increase in autophagy flux. In particular, an intense LC3B and p62 staining was observed in proliferating endothelial cells, in neovascular tufts, and photoreceptors. After a single intraocular injection of Rapamycin at P12 OIR, a decreased neovascular area and vascular endothelial growth factor (VEGF) protein expression were observed at P17 OIR. In addition, whereas the increased expression of glial fibrillary acidic protein (GFAP) was reversed at P26 OIR, the functional alterations persisted. Using a similar therapeutic schedule, next we analyzed the effect of anti-VEGF therapy on autophagy flux. Like Rapamycin, VEGF inhibitor treatment not only reduced the amount of neovascular tufts, but also activated autophagy flux at P17 OIR, mainly in ganglion cell layer (GCL) and inner nuclear layer (INL). Finally, the effects of the disruption of autophagy by Spautin-1, were evaluated at vascular, glial and neuronal levels. After a single dose of Spautin-1, Western blot analysis showed a significant decrease in LC3B II and p62 protein expression at P13 OIR, returning both autophagy markers to OIR control levels at P17. In addition, neither gliosis nor functional alterations were attenuated. In line with these results, TUNEL staining showed a slight increase in the number of positive cells in the outer nuclear layer (ONL) at P17 OIR. Overall, our results demonstrate that all treatments of induction or inhibition of the autophagic flux, administered at P12, were unable to completely reverse the neuronal damage. In conclusion, our study highlights the importance to consider the autophagy participation in retinal damage and survival in order to design more effective treatments to help preserve retinal functionality and prevent gliosis.