scholarly journals mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

2020 ◽  
Author(s):  
Sanjar Batirovich Madrakhimov ◽  
Jin Young Yang ◽  
Jin Ha Kim ◽  
Jung Woo Han ◽  
Tae Kwann Park
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Tissue Samples ◽  
Glucose Transporter 1 ◽  
Subcutaneous Injections

Abstract Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin (two daily subcutaneous injections at a dose of 200 mg/kg of body weight during the last 7 full days of the experiment and the morning of the 8th day, 3 h before sacrifice) or rapamycin (daily intraperitoneal injections, at a dose of 3mg/kg for the same period as for phlorizin treatment). The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin (two daily subcutaneous injections during the last 10 full days of the experiment and the morning of the 11th day, 3 h before sacrifice) or MHY1485 (daily i.p. injections, at a dose of 10 mg/kg for the same period as for phlorizin treatment). Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

scholarly journals mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sanjar Batirovich Madrakhimov ◽  
Jin Young Yang ◽  
Jin Ha Kim ◽  
Jung Woo Han ◽  
Tae Kwann Park
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Tissue Samples ◽  
Glucose Transporter 1 ◽  
Subcutaneous Injections

Abstract Background Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in DR. Methods Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of DR was investigated in 1-month-diabetic mice treated with phlorizin (two daily subcutaneous injections at a dose of 200 mg/kg of body weight during the last 7 full days of the experiment and the morning of the 8th day, 3 h before sacrifice) or rapamycin (daily intraperitoneal injections, at a dose of 3 mg/kg for the same period as for phlorizin treatment). The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin (two daily subcutaneous injections during the last 10 full days of the experiment and the morning of the 11th day, 3 h before sacrifice) or MHY1485 (daily i.p. injections, at a dose of 10 mg/kg for the same period as for phlorizin treatment). Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis. Results mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker—cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer, as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

scholarly journals mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

2020 ◽  
Author(s):  
Sanjar Batirovich Madrakhimov ◽  
Jin Young Yang ◽  
Jin Ha Kim ◽  
Jung Woo Han ◽  
Tae Kwann Park
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Tissue Samples ◽  
Glucose Transporter 1 ◽  
Apoptosis Pathway

Abstract Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin or rapamycin. The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin or MHY1485. Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

scholarly journals Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuhong Fu ◽  
Ying Wang ◽  
Xinyuan Gao ◽  
Huiyao Li ◽  
Yue Yuan
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Control Group ◽  
Diabetic Patients ◽  
Retinal Ganglion ◽  
Glucose Levels ◽  
Dynamic Expression

Background. Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods. To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results. Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P<0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r=0.7424), P<0.01. HDAC3 was positively correlated with LC3B expression (r=0.7336), P<0.01. Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.

Monocular enucleation prevents retinal ganglion-cell loss following neonatal visual cortex damage in cats

1998 ◽  
Vol 15 (6) ◽  
pp. 1097-1105 ◽  
Author(s):  
KURT R. ILLIG ◽  
VON R. KING ◽  
PETER D. SPEAR
Keyword(s):  
Visual Cortex ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Cell Loss ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Medium Size ◽  
Retinal Ganglion ◽  
Retrograde Degeneration ◽  
Monocular Enucleation ◽  
Binocular Interactions

Damage to primary visual cortex (VC) in young cats leads to severe retrograde degeneration of the dorsal lateral geniculate nucleus (dLGN) and selective transneuronal retrograde degeneration of a class of retinal ganglion cells (RGCs) that have a medium-size soma. Previous studies have shown that “programmed” RGC death associated with normal development in one eye can be attenuated by removal of the other eye, suggesting that binocular interactions can influence developmental RGC death. The present study investigated whether removal of one eye also attenuates the ganglion cell loss that accompanies an early VC lesion. Five one-week-old cats received a unilateral VC lesion (areas 17, 18, and 19), and three of these cats also underwent monocular enucleation at the same time. Two normal control animals also were examined. RGC measurements were made from flat-mounted retinae when the animals were 5 weeks old. Sampling was restricted to a retinal area corresponding to the retinotopic representation included in the VC lesion. Results indicate that there is a marked loss of medium-size RGCs in the hemiretinae projecting to the damaged hemisphere in cats that received a VC lesion alone. However, there is no such loss in VC-lesion animals that also have a monocular enucleation. These results indicate that the transneuronal RGC loss that occurs after an early visual cortex lesion can be influenced by binocular interactions.

scholarly journals Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

2020 ◽  
Vol 21 (7) ◽  
pp. 2351
Author(s):  
María Constanza Potilinski ◽  
Valeria Lorenc ◽  
Sofía Perisset ◽  
Juan Eduardo Gallo
Keyword(s):  
Diabetic Retinopathy ◽  
Signaling Pathways ◽  
Structural Changes ◽  
Ganglion Cells ◽  
Cell Loss ◽  
The Body ◽  
Retinal Ganglion ◽  
Therapeutic Approaches ◽  
Function Impairment ◽  
Alpha 1 Antitrypsin

Diabetes produces several changes in the body triggered by high glycemia. Some of these changes include altered metabolism, structural changes in blood vessels and chronic inflammation. The eye and particularly the retinal ganglion cells (RGCs) are not spared, and the changes eventually lead to cell loss and visual function impairment. Understanding the mechanisms resulting in RGC damage and loss from diabetic retinopathy is essential to find an effective treatment. This review focuses mainly on the signaling pathways and molecules involved in RGC loss and the potential therapeutic approaches for the prevention of this cell death. Throughout the manuscript it became evident that multiple factors of different kind are responsible for RGC damage. This shows that new therapeutic agents targeting several factors at the same time are needed. Alpha-1 antitrypsin as an anti-inflammatory agent may become a suitable option for the treatment of RGC loss because of its beneficial interaction with several signaling pathways involved in RGC injury and inflammation. In conclusion, alpha-1 antitrypsin may become a potential therapeutic agent for the treatment of RGC loss and processes behind diabetic retinopathy.

scholarly journals Article Commentary: Retinal Ganglion Cell Loss in Diabetes Associated with Elevated Homocysteine

2009 ◽  
Vol 1 ◽  
pp. OED.S3417 ◽  
Author(s):  
Kenneth S. Shindler
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Ganglion Cell Layer ◽  
Ganglion Cells ◽  
Cell Layer ◽  
Cell Loss ◽  
Diabetic Patients ◽  
Retinal Ganglion ◽  
Heterozygous Deletion ◽  
Retinal Pathology

A number of studies have suggested that homocysteine may be a contributing factor to development of retinopathy in diabetic patients based on observed correlations between elevated homocysteine levels and the presence of retinopathy. The significance of such a correlation remains to be determined, and potential mechanisms by which homocysteine might induce retinopathy have not been well characterized. Ganapathy and colleagues 1 used mutant mice that have endogenously elevated homocysteine levels due to heterozygous deletion of the cystathionine-β-synthase gene to examine changes in retinal pathology following induction of diabetes. Their finding that elevated homocysteine levels hastens loss of cells in the retinal ganglion cell layer suggests that toxicity to ganglion cells may warrant further investigation as a potential mechanism of homocysteine enhanced susceptibility to diabetic retinopathy.

Retinal Ganglion Cell Loss in Children With Type 1 Diabetes Mellitus Without Diabetic Retinopathy

2017 ◽  
Vol 48 (6) ◽  
pp. 473-477 ◽  
Author(s):  
Omer Karti ◽  
Ozlem Nalbantoglu ◽  
Saygin Abali ◽  
Ziya Ayhan ◽  
Selma Tunc ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Diabetic Retinopathy ◽  
Type 1 Diabetes Mellitus ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Cell Loss ◽  
Retinal Ganglion

The S1P1 receptor-selective agonist CYM-5442 protects retinal ganglion cells in endothelin-1 induced retinal ganglion cell loss

2017 ◽  
Vol 164 ◽  
pp. 37-45 ◽  
Author(s):  
Román Blanco ◽  
Gema Martínez-Navarrete ◽  
Francisco J. Valiente-Soriano ◽  
Marcelino Avilés-Trigueros ◽  
Consuelo Pérez-Rico ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Endothelin 1 ◽  
S1p1 Receptor ◽  
Selective Agonist

scholarly journals IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Ao-Wang Qiu ◽  
Da-Rui Huang ◽  
Bin Li ◽  
Yuan Fang ◽  
Wei-Wei Zhang ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
T Lymphocytes ◽  
Retinal Ganglion Cells ◽  
Neuronal Death ◽  
Ganglion Cells ◽  
Müller Cells ◽  
Retinal Ganglion ◽  
Muller Cells ◽  
Diabetic Mice

AbstractDiabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.

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