Development of novel urine biomarkers for diabetic kidney disease by focusing on the regulation of renal megalin expression.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07944
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kitasato University
• Principal Investigator: Kurosaki Yoshifumi 北里大学, 医療衛生学部, 講師 (20602030)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 糖尿病性腎症 / メガリン / バイオマーカー / 酸化ストレス / マイクロRNA

Outline of Final Research Achievements

Present study clarified the increase in megalin expression induced by oxidative stress was negatively regulated by megalin regulated intramembrane proteolysis (RIP). Interestingly, intracellular megalin COOH-terminal fragment (MCTF) excretion in medium was increased by hydrogen peroxide treatment in a dose-dependent manner. Furthermore, megalin MCTF excretion in the urine of STZ-induced diabetes was significantly increased compared to sham rats. Next, we evaluated if micro RNA (miRNA) related to the megalin negative feedback system. Although miRNA-148b is known to be one of the regulator for megalin expression, hydrogen peroxide treatment did not affect the expression of miRNA-148b. Then we conducted a comprehensive miRNA array to find megalin-related and oxidative-induced miRNA. Two miRNA was picked up for candidates for megalin regulator. We would expect those miRNA could be useful as urine biomarker for diabetes nephropathy.

Free Research Field

臨床化学

Academic Significance and Societal Importance of the Research Achievements

これまでの研究で、糖尿病性腎症の初期に腎尿細管におけるメガリンの発現が上昇することを明らかにしてきた。本研究では、このメガリンの上昇に対して抑制的に作用するメガリン制御的膜内切断（RIP)に関連する分子MCTFが、尿中に早期に検出される可能性を見出した。糖尿病性腎症は透析患者の原因疾患で最も多いため、MCTFを活用した糖尿病性腎症の早期診断は透析患者減少に寄与し、患者QOLの向上や透析に要する医療費の削減などに寄与することが期待される。