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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• 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 / ミトコンドリア / 酸化ストレス

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.

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。

Research Products

• [Journal Article] Hypoglycemia Induces Mitochondrial Reactive Oxygen Species Production Through Increased Fatty Acid Oxidation and Promotes Retinal Vascular Permeability in Diabetic Mice (2020)
  • Author(s): Yoshinaga Ayaka、Kajihara Nobuhiro、Kukidome Daisuke、Motoshima Hiroyuki、Matsumura Takeshi、Nishikawa Takeshi、Araki Eiichi
  • Journal Title: Antioxidants & Redox Signaling Volume: Online ahead of print Issue: 16 Pages: 1245-1259
  • DOI: 10.1089/ars.2019.8008
  • Peer Reviewed / Open Access
• [Presentation] 低血糖下の血管内皮細胞における脂肪酸酸化を介したミトコンドリア由来活性酸素種の産生増加－糖尿病合併症新規メカニズムの提唱－ (2021)
  • Author(s): 梶原伸宏
  • Organizer: 第71回日本体質医学会総会
• [Presentation] 低血糖による糖尿病網膜症の発症・進展に対するミトコンドリア由来活性酸素種 (mtROS) の関与 (2020)
  • Author(s): 吉永礼香，梶原伸宏，久木留大介，本島寛之，松村剛，西川武志，荒木栄一
  • Organizer: 第63回日本糖尿病学会年次学術集会 2020/10/5-16,滋賀 WEB開催,若手研究奨励賞審査口演
• [Presentation] 脂肪酸酸化を介した低血糖誘導ミトコンドリア由来活性酸素種 (mtROS) の血液網膜関門への影響の検討 (2020)
  • Author(s): 3.吉永礼香，梶原伸宏，久木留大介，本島寛之，松村剛，西川武志，荒木栄一
  • Organizer: 第35回日本糖尿病合併症学会・第26回日本糖尿病眼学会総会 2020/12/7-21,金沢 WEB開催,ワークショップ