mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy
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 ta...
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doaj-ef5afa434ef340629f6eeb184de447262021-03-11T11:59:35ZengBMCCell Communication and Signaling1478-811X2021-02-0119111610.1186/s12964-020-00698-4mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathySanjar Batirovich Madrakhimov0Jin Young Yang1Jin Ha Kim2Jung Woo Han3Tae Kwann Park4Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Bucheon HospitalDepartment of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Bucheon HospitalDepartment of Ophthalmology, Soonchunhyang University Hospital BucheonDepartment of Ophthalmology, Soonchunhyang University Hospital BucheonDepartment of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Bucheon HospitalAbstract 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. Video Abstracthttps://doi.org/10.1186/s12964-020-00698-4Diabetic retinopathyNeurodegenerationAutophagyApoptosisThe mechanistic target of rapamycin (mTOR) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sanjar Batirovich Madrakhimov Jin Young Yang Jin Ha Kim Jung Woo Han Tae Kwann Park |
spellingShingle |
Sanjar Batirovich Madrakhimov Jin Young Yang Jin Ha Kim Jung Woo Han Tae Kwann Park mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy Cell Communication and Signaling Diabetic retinopathy Neurodegeneration Autophagy Apoptosis The mechanistic target of rapamycin (mTOR) |
author_facet |
Sanjar Batirovich Madrakhimov Jin Young Yang Jin Ha Kim Jung Woo Han Tae Kwann Park |
author_sort |
Sanjar Batirovich Madrakhimov |
title |
mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
title_short |
mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
title_full |
mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
title_fullStr |
mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
title_full_unstemmed |
mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
title_sort |
mtor-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy |
publisher |
BMC |
series |
Cell Communication and Signaling |
issn |
1478-811X |
publishDate |
2021-02-01 |
description |
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. Video Abstract |
topic |
Diabetic retinopathy Neurodegeneration Autophagy Apoptosis The mechanistic target of rapamycin (mTOR) |
url |
https://doi.org/10.1186/s12964-020-00698-4 |
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