Protective or Harmful: The Dual Roles of Autophagy in Diabetic Retinopathy

Abstract

Autophagy is a self-degradative pathway involving intracellular substance degradation and recycling. Recently, this process has attracted a great deal of attention for its fundamental effect on physiological processes in cells, tissues, and the maintenance of organismal homeostasis. Dysregulation of autophagy occurs in some diseases, including immune disease, cancer, and neurodegenerative conditions. Diabetic retinopathy (DR), as a serious microvascular complication of diabetes, is the main cause of visual loss in working-age adults worldwide. The pathogenic mechanisms of DR are thought to be associated with accumulation of oxidative stress, retinal cell apoptosis, inflammatory response, endoplasmic reticulum (ER) stress, and nutrient starvation. These factors are closely related to the regulation of autophagy under pathological conditions. Increasing evidence has demonstrated the potential role of autophagy in the progression of DR through different pathways. However, to date this role is not understood, and whether the altered level of autophagy flux protects DR, or instead aggravates the progression, needs to be explored. In this review, we explore the alterations and functions of autophagy in different retinal cells and tissues under DR conditions, and explain the mechanisms involved in DR progression. We aim to provide a basis on which DR associated stress-modulated autophagy may be understood, and to suggest novel targets for future therapeutic intervention in DR.

Autophagy: A Novel Pharmacological Target in Diabetic Retinopathy

“…Autophagy in DR has become an area of intense research, however, despite the studies currently available, the question of whether autophagy is counteracting or favoring the evolution of DR remains unclear. Furthermore, controversial results have often been reported in terms of the type of autophagy modulation induced by hyperglycemia (induction vs impairment), in both in vitro and in vivo models (Gong et al, 2021). However, most evidence suggests that autophagy may act with a damage/time-dependent double action (Figure 2).…”

Nutraceutical Strategy to Counteract Eye Neurodegeneration and Oxidative Stress in Drosophila melanogaster Fed with High-Sugar Diet

“…The altered balance of apoptosis and autophagy plays a crucial (and well conserved) role in visual system damages across species [ 11 , 13 , 20 , 53 ]. There is evidence that enhanced autophagy could protect retinal cells under diabetic conditions by inhibiting apoptosis induced by DR stress [ 21 ]. Since neuronal defects and altered apoptosis/autophagy machinery has been observed in our system [ 22 ] as well as in the mouse retina of early DR and oxygen-induced retinopathy models [ 17 , 19 ], we suggest that proper autophagy induced by Lisosan G is a key aspect in the hyperglycemic fly eye to counteract neurodegenerative/functional features.…”

“…Emerging evidence reveals that oxidative stress-induced disruption of autophagy in retinal cells is closely related to the pathogenesis of DR [ 21 ]. In this context, autophagy can prevent cells from oxidative stress by diminishing harmful intracellular materials.…”

“…Although the mechanisms by which ROS influence neuronal damage in DR are still not fully understood [ 4 , 5 , 6 ], the most important histological feature during hyperglycemia and DR at early stages is neuronal apoptosis [ 7 , 8 , 9 ]. Alterations of the catabolic pathway autophagy also play a key role in different retina dysfunctions, including DR [ 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Recently, we used the fruit fly Drosophila melanogaster fed with high-sucrose diets as an in vivo model of hyperglycemia-induced neuronal damage [ 22 ].…”

Eicosapentaenoic Acid-Induced Autophagy Attenuates Intervertebral Disc Degeneration by Suppressing Endoplasmic Reticulum Stress, Extracellular Matrix Degradation, and Apoptosis

“…However, the relationship between autophagy and ER-stress remains a mystery. Some researchers have proposed that ER stress can inhibit autophagy by promoting mechanistic target of rapamycin complex-1 (mTORC1) ( Gong et al, 2021 ). On the contrary, transcription factors such as ATF4 and XBP have been reported to enhance autophagy during ER-stress ( Guo and Li, 2014 ; Xia et al, 2021 ).…”