Contribution of USF1 on development of diabetic kidney disease and the drug discovery of PI polyamides to block the USF1 binding

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08599
• 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: Nihon University
• Principal Investigator: ABE Masanori 日本大学, 医学部, 教授 (70459890)
• Co-Investigator(Kenkyū-buntansha): 松本 宜明 日本大学, 薬学部, 教授 (10199896) ; 福田 昇 日本大学, 総合科学研究所, 教授 (40267050)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 糖尿病性腎症 / PIポリアミド / 転写因子 / USF1

Outline of Final Research Achievements

We designed, synthesized and examined effects of PI polyamides to block a transcription factor USF1 bindings on human TGF-β1 promoter as a novel medicine on diabetic kidney disease. PI polyamides targeting USF1 binding significantly suppressed expressions of TGF-β1 and osteopontin in human mesangial cells stimulated with high glucose, by which a lead compound was determined. High glucose significantly increased expressions of TGF-β1 and αSMA in human renal tubular cells. The lead PI polyamide significantly suppressed αSMA expression and the cellular morphological changes as EMT. These findings indicate that the USF1 blocking PI polyamide inhibits expression of TGF-β1 and EMT phenomen and will be a novel medicine for diabetic kidney disease.

Free Research Field

腎臓病学

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎症(DKD)は末期腎不全の主たる原因であるが未だに根治薬が無い。PIポリアミドは転写因子の遺伝子結合を抑制する中分子ペプチド医薬である。今回、DKDの進展に関わる転写因子USF1のTGF-β1遺伝子結合を抑制するPIポリアミドを設計合成し、創薬開発した。USF1　PIポリアミドが高糖条件でのメサンギウム(HMC)細胞のTGF-β1発現、増殖抑制を抑制し、近位尿細管細胞のEMT現象を抑制し、USF1 PIポリアミドがDKDでの腎線維化、進展を抑制した事は、DKDの新規治療薬として医療社会的意義は大きい。