Defective Autophagy in Diabetic Retinopathy

Faria, Jacqueline M. Lopes de; Duarte, Diego Andreazzi; Montemurro, Chiara; Papadimitriou, Alexandros; Consonni, Sílvio Roberto; Faria, José B. Lopes de

doi:10.1167/iovs.16-19197

Cited by 96 publications

(101 citation statements)

References 35 publications

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“…Although anti-VEGF therapeutic strategies have been employed thus far, the involvement of additional cellular factors 30 and symptoms beyond angiogenesis 2,27,29 show that neovascular retinal diseases are multifactorial conditions for which currently available treatments may be inadequate to address. Additionally, these treatments require frequent administration on a long-term basis, 3 from which other issues may arise, including safety concerns.…”

Section: Discussionmentioning

confidence: 99%

“…Although the links between cell death and pathological retinal angiogenesis have yet to be fully elucidated, including the exact mechanism(s) involved, increased apoptosis has been implicated in the release of VEGF in proliferative DR (PDR). 29 TUNEL-positive cells were observed in the inner and outer nuclear layers of the untreated (16.6 ± 4.2), mocktreated (17.4 ± 5.6), and control shRNA-treated (17.6 ± 3.6) groups of the rat OIR model (Fig. 4A).…”

Section: Antiapoptotic Ability Of Raav2-shmtor-gfpmentioning

confidence: 98%

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Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Lee

Chang²,

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee SHS, Chang H, Kim JH, et al. Inhibition of mTOR via an AAV-Delivered shRNA tested in a rat OIR model as a potential antiangiogenic gene therapy. Invest Ophthalmol Vis Sci. 2020;61(2):45. https://doi.org/10.1167/iovs.61.2.45 PURPOSE.Recent studies have shown that inhibitors of the mechanistic target of rapamycin (mTOR) play important roles in proliferating endothelial cells within the retinal vasculature. Here we explore the effects of inhibiting mTOR as a potential gene therapeutic against pathological retinal angiogenesis in a rat model of oxygen-induced retinopathy (OIR). METHODS.Sprague-Dawley pups were used to generate the OIR model, with a recombinant adeno-associated virus expressing an shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection on returning the rats to normoxia, with appropriate controls. Immunohistochemistry and TUNEL assays, as well as fluorescein angiography, were performed on transverse retinal sections and flat mounts, respectively, to determine the in vivo effects of mTOR inhibition. RESULTS.Compared with normal control rats, as well as OIR model animals that were either untreated (20.95 ± 6.85), mock-treated (14.50 ± 2.47), or injected with a control short hairpin RNA (shRNA)-containing virus vector (16.64 ± 4.92), rAAV2-shmTOR-GFP (4.28 ± 2.86, P = 0.00103) treatment resulted in dramatically reduced neovascularization as a percentage of total retinal area. These results mirrored quantifications of retinal avascular area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly greater therapeutic efficacy than the other treatments. The virus vector was additionally shown to reduce inflammatory cell infiltration into retinal tissue and possess antiapoptotic properties, both these processes having been implicated in the pathophysiology of angiogenic retinal disorders. CONCLUSIONS.Taken together, these results demonstrate the strong promise of rAAV2-shmTOR-GFP as an effective and convenient gene therapy for the treatment of neovascular retinal diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Antiapoptotic Ability Of Raav2-shmtor-gfpmentioning

confidence: 98%

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Lee

Chang²,

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…In addition, autophagy inhibition reduced the activation of Müller cells and inhibited astrogliosis in damaged retinas, suggesting that the inhibition of autophagy prevents Müller cell activity during ischemia/reperfusion injury [58]. Lopes de Faria et al [59] reported that high glucose upregulated autophagy in retinal Müller cells and induced lysosomal impairment, which represent early events in the pathogenesis of diabetic retinopathy.…”

Section: Autophagy In Müller Cellsmentioning

confidence: 99%

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

Lin

2018

Ophthalmic Res

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Autophagy is a lysosomal degradation process that maintains cellular homeostasis by removing dysfunctional organelles and unfolded proteins. Increasing evidence has shown that autophagy proteins are involved in retinal physiology and pathology and that defective autophagy contributes to retinal degeneration. In retinal diseases, autophagy plays a dual role: promoting retinal cell survival and death. Autophagy at a normal level helps retinal cells defend themselves against harmful stress; however, excessive autophagy results in retinal deterioration. Both synergistic and antagonistic roles of autophagy and apoptosis in the retina have been reported in the literature. In this review, we summarize the roles of autophagy in the development of the retina and retinal diseases. This review highlights the importance of autophagy in retinal diseases, and targeting autophagy may provide a new therapeutic approach for retinal diseases.

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“…However, this catabolic process cannot reach the final stage (degradation of the cargo) because of an increase in the lysosomal pH and a decrease in lysosomal enzyme activity. Treatments with autophagy inductors, such as rapamycin, have restored the normal flux and prevented the activation of apoptosis (Lopes de Faria et al., ).…”

Section: Antioxidant Pathwaysmentioning

confidence: 99%

A journey into the retina: Müller glia commanding survival and death

Subirada

Paz

Ridano

et al. 2018

Eur J of Neuroscience

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Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?

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Defective Autophagy in Diabetic Retinopathy

Cited by 96 publications

References 35 publications

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

A journey into the retina: Müller glia commanding survival and death

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