Repair and regeneration of proximal tubular cells by inhibiting proxyl hydroxylases

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tohoku University (2021-2022); The University of Tokyo (2020)
• Principal Investigator: Tanaka Tetsuhiro 東北大学, 医学系研究科, 教授 (90508079)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 低酸素 / プロリン水酸化酵素 / 低酸素誘導因子 / AKI-CKD移行

Outline of Final Research Achievements

This study investigated a possible role of HIF1 in proximal tubules in a AKI-CKD transition model. Tamoxifen- inducible, proximal tubular- specific prolyl hydroxylase knockout (Ndrg1-CreERT2/Phd1,2,3cKO) mice were subjected to bilateral ischemia-reperfusion injury (IRI). Tamoxifen was given in the recovery phase to activate HIF1, and histological analyses were carried out at day 28. In the tamoxifen-treated group (IRI/Tam+), serum creatinine levels and albuminuria were significantly lower than the control (IRI/Tam-) group, and renal fibrosis was less severe. Mechanistically, the number of Ki-67- positive, proliferating proximal tubular cells was larger in the IRI/Tam+ group, and there was an increase in phosphorylated histone H3. These findings suggest that proximal tubular HIF1 contributes to ameliorating AKI-CKD transition by facilitating proliferation of tubular epithelial cells and reducing the production of inflammatory cytokines and fibrotic factors in the G2/M cells.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

AKIは古典的には短時間で急激に腎機能が低下する一過性の病態と考えられてきたが、近年の疫学研究によって、AKIはCKDへの移行リスクが高く、末期腎不全リスクも3.1倍高まることが明らかになった。しかしながら本病態に対して確立された治療法は存在しない。本研究の成果は上記のAKI-CKD移行に対して、近位尿細管における低酸素誘導因子HIF１の活性化が障害軽減をもたらす可能性を示唆しており、将来の新規治療法の開発や実効的な医療介入につながることが期待される。