Diabetic retinopathy (DR) is a common microvascular complication in patients with diabetes leading to a sudden and debilitating impact on visual acuity and eventually blindness. Advanced stages of DR are characterized by the growth of abnormal retinal blood vessels secondary to ischemia, whilst precocious stages are linked to altered glutamate excitation, reduced trophic factor signaling, oxidative stress, and neuro-inflammation. Although these alterations are among the many potential causes of retinal neuronal cell death, understanding of neurodegenerative mechanisms in the preproliferative stage of diabetic retinopathy is still unclear and no treatment is currently directed towards this stage. We and others have previously showed that estradiol is neuroprotective against ischemic insult and glutamate- or oxidative-mediated retinal cell death. We also found that the intraocular injection of 17?-estradiol regulates small heat shock proteins involved in preventing aggregation of denatured or unfolded proteins (D'Anna C et al., Proteomics 2011, 11, 986-90). Using a STZ rat model of diabetes, we here investigated the autophagic pathway along with mitochondrial dysfunction and apoptotic cell death in retinas at different times from the onset of diabetes and following or not the intraocular injection of 17?-estradiol. After 7 days of diabetes, there were changes in autophagic markers, such as LC3II/LC3I ratio and p62, as well as in receptor adapters involved in mitophagy, including parkin and BINP3, that suggested a blockade of autophagosomal-lysosomal flux. Consistently, accumulation of polyubiquitinated substrates and mitochondrial oxidative stress were early detected. Neuronal ganglion cells of diabetic retinas primarily showed co-localization of LC3 and TUNEL staining, indicating an initial cross-talk between autophagy and apoptosis. At the early stage of diabetic retinopathy, one week of 17?- estradiol intraocularly injected reverted autophagic dysfunction and apoptosis. These results support the hypothesis that advanced neurodegenerative events, likely related to autophagy/mitophagy, occur in the preproliferative diabetic retinopathy and the local treatment with estradiol may be a potential neuroprotective strategy
Autophagy impairment in the preproliferative diabetic retinophaty: A new target for estradiol prevention
C CASCIO;D RUSSO;I DEIDDA;G GALIZZI;
2014
Abstract
Diabetic retinopathy (DR) is a common microvascular complication in patients with diabetes leading to a sudden and debilitating impact on visual acuity and eventually blindness. Advanced stages of DR are characterized by the growth of abnormal retinal blood vessels secondary to ischemia, whilst precocious stages are linked to altered glutamate excitation, reduced trophic factor signaling, oxidative stress, and neuro-inflammation. Although these alterations are among the many potential causes of retinal neuronal cell death, understanding of neurodegenerative mechanisms in the preproliferative stage of diabetic retinopathy is still unclear and no treatment is currently directed towards this stage. We and others have previously showed that estradiol is neuroprotective against ischemic insult and glutamate- or oxidative-mediated retinal cell death. We also found that the intraocular injection of 17?-estradiol regulates small heat shock proteins involved in preventing aggregation of denatured or unfolded proteins (D'Anna C et al., Proteomics 2011, 11, 986-90). Using a STZ rat model of diabetes, we here investigated the autophagic pathway along with mitochondrial dysfunction and apoptotic cell death in retinas at different times from the onset of diabetes and following or not the intraocular injection of 17?-estradiol. After 7 days of diabetes, there were changes in autophagic markers, such as LC3II/LC3I ratio and p62, as well as in receptor adapters involved in mitophagy, including parkin and BINP3, that suggested a blockade of autophagosomal-lysosomal flux. Consistently, accumulation of polyubiquitinated substrates and mitochondrial oxidative stress were early detected. Neuronal ganglion cells of diabetic retinas primarily showed co-localization of LC3 and TUNEL staining, indicating an initial cross-talk between autophagy and apoptosis. At the early stage of diabetic retinopathy, one week of 17?- estradiol intraocularly injected reverted autophagic dysfunction and apoptosis. These results support the hypothesis that advanced neurodegenerative events, likely related to autophagy/mitophagy, occur in the preproliferative diabetic retinopathy and the local treatment with estradiol may be a potential neuroprotective strategyI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
