2023 Fiscal Year Final Research Report
Role of Nrf2 in renal gluconeogenesis and clarification of the control mechanism
| Project/Area Number |
21K11667
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Ogawa Susumu 東北大学, 高度教養教育・学生支援機構, 准教授 (20323016)
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| Co-Investigator(Kenkyū-buntansha) |
本橋 ほづみ 東北大学, 加齢医学研究所, 教授 (00282351)
西山 成 香川大学, 医学部, 教授 (10325334)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | oxidative stress / Nrf2 / renal gluconeogenesis / PEPCK / Glutamate / G6Pase / lactate |
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| Outline of Final Research Achievements |
We divided SD rats into the following five groups: (1) normal, (2) Streptozocin (STZ) diabetes, (3) STZ diabetes + tempol, (4) STZ diabetes + bardoxolone methyl, and (5) STZ diabetes + halofuginone. We measured changes in blood glucose level in the renal arteries and veins, as well as gluconeogenesis-related substances. Our results found the artery/vein ratio to be higher in the (2) than in the (1), but lower in the (3) and (4), which showed levels similar to that of the (1). Renal citrate and malic acid were higher in the (3) but were below (1) in the (4). PEPCK was significantly higher in the (3), while phosphoenolpyruvic acid (PEP) was below (1) in the (3) and (4), particularly so in the (4). G-6-P was higher in the (2) and (3), and significantly lower in the (4).
Our results show oxidative stress to have expanded the pathway from PEP to G-6-P and ultimately to glucose. Nrf2 inhibited glucose synthesis by increasing the synthesis of lactic acid and uric acid from PEP.
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| Free Research Field |
腎臓生理学、糖尿病・代謝学
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| Academic Significance and Societal Importance of the Research Achievements |
学術的意義：腎臓は血液中ブドウ糖の10%以上を供給する臓器であるが、その制御メカニズムは不明であった。本研究により①そのブドウ糖供給は腎酸化ストレス増大により増大し、酸化ストレス増大により誘導される転写因子Nrf2により抑制されることが解明された。さらにNrf2は酸化ストレスを抑制することでブドウ糖産生を抑制しているのではなく、糖新生経路における酸化ストレスの作用部位とは異なる部位を変化させることで糖新生を抑制することが明らかにされた。この学術的意義は大きい。
社会的意義：腎糖新生制御メカニズムの解明は、新しい糖尿病治療薬の開発につながる可能性があり、その社会的意義は大きい。
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