Exploration of the role of Keap1-Nrf2 signaling pathway in renal fibrosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08685
• 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: Jichi Medical University
• Principal Investigator: Nagata Daisuke 自治医科大学, 医学部, 教授 (40393194)
• Co-Investigator(Kenkyū-buntansha): 前嶋 明人 自治医科大学, 医学部, 准教授 (70431707)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: KEAP1-Nrf2系 / 腎間質線維化 / バルドキソロンメチル / Nrf2活性化 / 片側尿細管結紮モデル

Outline of Final Research Achievements

Two-week unilateral tubular ligation (UUO) was performed on C57BL / 6 mice, and C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), which has the effect of activating Nrf2, was administered. The fibrotic area was reduced when fibrosis was evaluated by Sirius red staining compared with the control. In this study, we generated conditional knock-out mice lacking Nrf2 in a tubular and endothelium-specific manner (Pax8-Cre / flox-Nrf2 and Tie2-Cre / flox-Nrf2, respectively). When a UUO model was created, the density of peritubular capillaries was not different from that of the control flox-Nrf2 mouse. However, Pax8-Cre / flox-Nrf2 mice significantly increased interstitial fibrosis compared to Tie2-Cre / flox-Nrf2 and flox-Nrf2 mice. When TGF-b and collagen I were evaluated by real-time PCR, these expressions increased. These results suggest that renal tubular Nrf2 activation could suppress renal interstitial fibrosis.

Free Research Field

腎臓病学

Academic Significance and Societal Importance of the Research Achievements

バルドキソロンメチルによりNrf2が活性化されると、腎間質線維化は抑制されることは以前の研究で明らかにされていたが、その機序の詳細や、腎臓のどの部位のNrf2の活性化が重要なのかは長期間不明のままであった。今回の研究で、それが尿細管におけるNrf2の活性がが重要であることが明確に示された。