Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes

Abstract

The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.

Role of Autophagy in Angiogenesis Induced by a High-Glucose Condition in RF/6A Cells

“…Nevertheless, the mechanisms of autophagy involved in DR may be complex and have not been conclusively established. Research showed a substantial increase in autophagic activity in retinal ganglion cells in mice with streptozotocin-induced diabetes, which indicates that cell death develops with the initial dysregulation of autophagy before the appearance of signs of vascular damage and without a strong involvement of apoptosis [27] . Further research revealed that autophagy has a dual role in DR: under mild stress, it is protective for human retinal capillary pericytes, while under more severe stress it promotes cell death [28] .…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Increasing evidence suggests that ROS induces the activation of NLRP3 inflammasome and enhances the secretion of IL‐1β (Zhang et al, ; Choe & Kim, ). In STZ‐induced diabetic mice, rod demise was accompanied by an increase in LC3A protein, a marker for autophagosomes (Mizushima & Yoshimori, ; Piano et al, ). Similarly, ARPE‐19 cells showed signs of autophagy together with ROS release in response to high‐glucose‐induced stress (Shi et al, ).…”

TXNIP regulates mitophagy in retinal Müller cells under high-glucose conditions: implications for diabetic retinopathy

“…15, 16 Of the many autophagy-related proteins (ATGs), LC3BII (ATG8) is required for the nucleation and elongation of the double membrane autophagophore. 17 LC3BI is conjugated with phosphatidylethanolamine (lipidation) to form LC3BII via a number of steps that involve ATG7 and ATG3, as well as ATG12, ATG5 and ATG16L.…”