Hypoglycemia induces mitochondrial reactive oxygen species production and promotes retinal vascular permeability

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15422
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: Kajihara Nobuhiro 熊本大学, 病院, 病院教員 (80814756)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: ミトコンドリア由来活性酸素種 / 低血糖 / 糖尿病網膜症 / 脂肪酸酸化 / 網膜血管内皮細胞 / 血管透過性

Outline of Final Research Achievements

I hypothesized that the mechanisms underlying hypoglycemia-induced diabetic retinopathy are associated with blood-retinal barrier (BRB) breakdown due to mitochondrial reactive oxygen species (mtROS) generation during hypoglycemia. Here, I aimed to determine whether hypoglycemia exacerbated mtROS production and induced BRB disruption. As the results, I observed that hypoglycemia induced mtROS production by increasing fatty acid oxidation (FAO), which was suppressed by overexpression of mitochondrial-specific manganese superoxide dismutase (MnSOD) in retinal endothelial cells. Furthermore, FAO blockade decreased the hypoglycemia-induced mtROS production. Recurrent hypoglycemia increased albumin leak in diabetic mice retina, which was suppressed in diabetic vascular endothelial cell-specific MnSOD transgenic mice.

Free Research Field

糖尿病合併症

Academic Significance and Societal Importance of the Research Achievements

低血糖時の網膜血管内皮細胞において脂肪酸酸化亢進を介してmtROS産生が増加すること、また低血糖由来mtROSがBRB破綻の一因になることを世界で初めて示した。低血糖時の脂肪酸酸化亢進の抑制は、低血糖による糖尿病網膜症発症・進展における新たな治療標的となりうると考えられた。