1. Academic Validation
  2. mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

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

  • Cell Commun Signal. 2021 Feb 26;19(1):29. doi: 10.1186/s12964-020-00698-4.
Sanjar Batirovich Madrakhimov  # 1 2 Jin Young Yang  # 1 2 Jin Ha Kim 3 Jung Woo Han 3 Tae Kwann Park 4 5 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Bucheon Hospital, Bucheon, South Korea.
  • 2 Laboratory for Translational Research On Retinal and Macular Degeneration, Soonchunhyang University Hospital Bucheon, Bucheon, South Korea.
  • 3 Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon, South Korea.
  • 4 Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Bucheon Hospital, Bucheon, South Korea. tkpark@schmc.ac.kr.
  • 5 Laboratory for Translational Research On Retinal and Macular Degeneration, Soonchunhyang University Hospital Bucheon, Bucheon, South Korea. tkpark@schmc.ac.kr.
  • 6 Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon, South Korea. tkpark@schmc.ac.kr.
  • 7 Department of Ophthalmology, College of Medicine, Soonchunhyang University, Choongchungnam-do, Cheonan, South Korea. tkpark@schmc.ac.kr.
  • 8 Department of Ophthalmology, College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea. tkpark@schmc.ac.kr.
  • 9 Ex Lumina Therapeutics and Technologies. Co., Ltd., Bucheon, South Korea. tkpark@schmc.ac.kr.
  • # Contributed equally.
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.

Keywords

Apoptosis; Autophagy; Diabetic retinopathy; Neurodegeneration; The mechanistic target of rapamycin (mTOR).

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