2006 Fiscal Year Final Research Report Summary
Molecular Mechanisms of Damage to Retinal Neuronal Cells in Diabetic Retinopathy and New Therapeutic Modalities
| Project/Area Number |
17591819
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Ophthalmology
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| Research Institution | Yamagata University |
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Principal Investigator |
YAMASHITA Hidetoshi Yamagata University, School of Medicine, Department of Ophthalmology and Visual Science, Professor, 医学部, 教授 (90158163)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Teiko Yamagata University, Hospital, Department of Ocular Cellular Engineering, Associate Professor, 医学部, 助教授 (00297706)
SATO Hiroaki Yamagata University, School of Medicine, Assistant, 医学部, 助手 (30344807)
KASHIWAGI Yoshiko Yamagata University Hospital, Hospital, Department of Ocular Cellular Engineering, Assistant Professor, 医学部, 客員助手 (90375345)
SATO Sakura Yamagata University, School of Medicine, Department of Ophthalmology and Visual Science, Fellow, 医学部, 医員 (60323169)
KANNO Chikako Yamagata University School of Medicine, School of Medicine, Department of Ophthalmology and Visual Science, Fellow, 医学部, 医員 (90375337)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Diabetic retinopathy / Retinal neuronal cell / Retinal vessel / Metabolic abnormalities of glucose / VEGF / Protection of Neuronal cells / Activin A / Apoptosis |
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| Research Abstract |
Diabetic retinopathy remains a significant cause of acquired visual loss in working-age adults worldwide. The incidence of diabetic retinopathy increases along with the increase of the number of diabetes mellitus patients, and it is mandatory to develop the new strategy of the protection of retinal neuronal cells to decrease the number of acquired visual loss patients due to diabetic retinopathy. To inquire this strategy, we have investigated the molecular mechanisms of the damage to retinal neuronal cells and to inhibit this process.
We clarified that the activation of protein kinase C β (PKC β ) and diacylglycerol kinase (DGK) contribute to the development and progression of diabetic retinopathy by affecting the retinal neuronal cells. The exposure to the high glucose level leaded to the de novo increase in the synthesis of diacylglycerol (DAG), which activated PKC β3 in the retinal neuronal cells and accelerated the production of vascular endothelial growth factor (VEGF). DGK catalyz
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es phosphorylation of DAG to phosphatidic acid (PA), controls DAG levels, and was stimulated after the exposure to the high glucose. We clarified that DGK a was related to the pathogenesis of diabetic retinopathy through VEGF expression both in 2 types of retinoblastoma cells and the retina of streptozotocin-induced diabetic rats as an animal model. In the pathogenesis of diabetic retinopathy, fibro-vascular membrane formation is important, and hyalocytes are involved in this process. We observed the expression of VEGF and interleukin6 (IL-6) was stimulated by the inflammatory cytokines (IL-1 α and β3, TNF-α ).
The mechanisms of retinal neuronal cell death : ActivinA is expressed in eyes and exerts certain effects on retinopathy. The effects of activinA on retinal neuronal cells were investigated using retinoblastoma (RB) cell lines. RB cell lines were used as the undifferentiated retinal cells, expressed activin receptors and cytoplasmic components for activin. The signal transduction pathway was confirmed by using Luciferase assay after the stimulation of activinA. Activin A signal was shown to induce apoptosis in RB cells. Taken together, high glucose condition and/or various cytokines may be related to the retinal neuronal cell damage including apoptosis. The inhibition of apoptosis may be the target to protect retinal neuronal cells. Less
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