Kidney specific local activation of Nrf2 and its effects on renal injury in mice

• Project/Area Number: 17K10155
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokai University
• Principal Investigator: NIIMURA Fumio 東海大学, 医学部, 准教授 (30282750)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腎障害 / 抗酸化防御機構 / 酸化ストレス / Keap1 / Nrf2 / シクロスポリン / 尿管結紮モデル / コンディショナルターゲティング / 近位尿細管 / 急性腎障害 / Cre-loxPシステム

Outline of Final Research Achievements

We generated a mouse strain in which Keap1 gene is inactivated only in renal straight proximal tubules by conditional targeting using Cre loxP system, thus resulting in kidney specific local activation of Nrf2 which plays a central role for antioxidant protection mechanisms. Renal injury was introduced in this mouse strain to see weather renal injury was ameliorated by the kidney specific local Nrf2 activation. We were unable to demonstrate the alleviation of cyclosporine A-induced renal damage in this mouse strain. However, the renal damage induced by unilateral ureteral obstruction was alleviated in this mouse strain as shown by renal histology and renal damage-related gene expressions.

Academic Significance and Societal Importance of the Research Achievements

抗酸化防御機構の破綻は腎障害の増悪につながるものの、抗酸化防御機構の活性化が腎障害の軽減につながるか否かについては未解決な部分が大きい。本研究では腎障害モデルによっては必ずしも明確な改善を見出せず、抗酸化防御機構活性化は治療戦略としての合理性はあるが、それが組織障害軽減に寄与するメカニズムは必ずしも単純ではないと考えられた。今後、抗酸化防御機構の活性化をより効果的に腎障害の軽減につなげるためには、他に何らかの工夫が必要であることを示唆する結果であった。