Elucidation of mechanism of the retina ganglion cell death against aldosterone neurotoxicity

• Project/Area Number: 17K11483
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Hiroshima University (2018-2019); Kagawa University (2017)
• Principal Investigator: Hirooka Kazuyuki 広島大学, 病院(医), 准教授 (10325350)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 緑内障 / 網膜神経節細胞 / アルドステロン / 視神経乳頭血流 / 血漿アルドステロン濃度 / 神経節細胞 / グルタミン酸 / 網膜血流

Outline of Final Research Achievements

We reported that the renin-angiotensin-aldosterone system (RAAS) appeared to play an important role with regard to the neuronal degeneration that occured in the retina. Glutamate excitotoxicity triggered by overactivation of the N-methyl-D-aspartate (NMDA) receptors may be a potential risk factor for retinal ganglion cell (RGC) death. Our findings show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.
We investigated the relationship between the plasma concentration of aldosterone and changes in the number of RGCs after systemic administration of aldosterone. There was a negative correlation between the plasma aldosterone concentration and the number of RGCs. Systemic administration of aldosterone caused a decrease in optic nerve head blood flow. Although the blood flow decrease was well correlated with RGC loss, the mild blood flow reduction indicates that retinal ischemia was unlikely to be the primary cause of RGC loss.

Academic Significance and Societal Importance of the Research Achievements

緑内障では網膜神経節細胞が障害されるが、この細胞死をもたらす経路を明らかにすることが、緑内障治療において重要である。我々は網膜神経節細胞死を引き起こす新しいメカニズムを明らかにした。さらに血液中のアルドステロンの濃度が高いほど、より多くの網膜神経節細胞が障害を受けることを今回明らかにしたが、これは従来から我々が報告してきたアルドステロンが網膜神経節細胞死を引き起こすことを一層明白にしたものである。今回の研究でアルドステロンによる網膜神経節細胞死のメカニズムが明らかになってきたことから、将来の治療法の開発に繋がり、結果として緑内障による失明を減らすことができるものと思われる。

Research Products

• [Journal Article] Gene expression changes in the retina after systemic administration of aldosterone (2018)
  • Author(s): Aoi Ono, Kazuyuki Hirooka, Yuki Nakano, Eri Nitta, Akira Nishiyama, Akitaka Tsujikawa
  • Journal Title: Japanese Journal of Ophthalmology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] The relationship between the renin-angiotensin-aldosterone system and NMDA receptor-mediated signal and the prevention of retinal ganglion cell death. (2017)
  • Author(s): Mamoru Kobayashi, Kazuyuki Hirooka, Aoi Ono, Yuki Nakano, Akira Nishiyama, Akitaka Tsujikawa
  • Journal Title: Investigative Ophthalmology & Visual Science Volume: 58 Pages: 1397-1403
  • Peer Reviewed
• [Presentation] アルドステロン全身投与によるラット視神経乳頭血流障害と網膜神経節細胞死との関係 (2019)
  • Author(s): 和田康史、東出 朋巳、阪口 仁一、長田 敦、廣岡 一行、杉山 和久)
  • Organizer: 日本緑内障学会
• [Presentation] 血中アルドステロン濃度と網膜神経節細胞数の関係 (2018)
  • Author(s): 廣岡一行、高砂縁、中野裕貴、小林守
  • Organizer: 第122回日本眼科学会総会
• [Presentation] Elevated plasma aldosterone levels is associated with a reduction in retinal ganglion cell survival (2018)
  • Author(s): Yukari Takasago, Kazuyuki Hirooka, Yuki Nakano, Mamoru Kobayashi
  • Organizer: Association Research in Vision and Ophthalmology
  • Int'l Joint Research
• [Presentation] アルドステロン全身投与によるラット視神経乳頭血流変化の検討 (2018)
  • Author(s): 和田康史、東出朋巳、阪口 仁一、長田 敦、 廣岡 一行、杉山 和久
  • Organizer: 第122回日本眼科学会総会
• [Presentation] 血漿アルドステロン濃度と網膜神経節細胞数の関係 (2018)
  • Author(s): 廣岡一行、高砂縁、中野裕貴、小林守、小野葵
  • Organizer: 第122回日本眼科学会総会
• [Presentation] 網膜神経節細胞死におけるレニン・アンジオテンシン系とＮＭＤＡ受容体シグナルの関連 (2017)
  • Author(s): 小林守、廣岡一行、小野葵、中野裕貴、辻川明孝
  • Organizer: 第121回日本眼科学会総会
• [Presentation] The relationship between the renin-angiotensin-aldosterone system and NMDA receptor-mediated signal and the prevention of retinal ganglion cell death. (2017)
  • Author(s): Kazuyuki Hirooka, Mamoru Kobayashi, Aoi Ono, Yuki Nakano, Akitaka Tsujikawa
  • Organizer: World Glaucoma Council
  • Int'l Joint Research