Suppression of progressive diabetic nephropathy stages by thrombomodulin

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16185
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Mie University
• Principal Investigator: Takeshita Atsuro 三重大学, 医学部附属病院, 助教 (10830490)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腎線維症 / 細菌叢 / 糖尿病性腎臓病 / トロンボモジュリン

Outline of Final Research Achievements

We previously reported that thrombomodulin (TM) has protective effects on kidney-specific human TGFβ1 overexpressing mice (TGFβ1-TG mice) that developed renal fibrosis. The aim of this study was to evaluate the effects of TM on diabetic kidney disease (DKD) and to identify the relevant mechanisms. Administration of human recombinant TM against streptozotocin (STZ)-induced diabetes suppressed glucose intolerance through inhibition of pancreatic β cell apoptosis and pancreatic inflammation. Next, STZ administration to TGFβ1-TG mice induced more severe renal fibrosis and decreased renal function compared to wild-type counterparts. Furthermore, treatment of vascular endothelial cell lines with bacteria derived peptide corisin induced increased apoptosis, decreased TM activity, and tissue factor activation.
We will continue to investigate the effects and mechanisms of TM on the pathogenesis of DKD, focusing on the relationship between TM and bacteria derived factors.

Free Research Field

慢性腎臓病

Academic Significance and Societal Importance of the Research Achievements

本研究はDKDの病態進行と臓器保護作用を有するトロンボモジュリンの関連を明らかにするためのものである。本研究で作成したDKDモデルマウスは片腎結紮モデル等と異なり低侵襲であり、ヒトのDKDの病態により近く、今後の新規薬剤開発や病態評価にとって有用であると考えられた。また、細菌由来ペプチドcorisinによるトロンボモジュリン活性低下の誘導は新たな知見であり、DKDにおいて説明の難しい進行速度の差にこうした細菌由来因子が関与している可能性がある。DKDの病態を考え、新規治療薬を開発する上で、TMと細菌由来因子の関連は重要と思われた。