Development of novel treatment approach for diabetic polyneuropathy targeting RAGE signaling and macrophage polarization

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16220
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Hirosaki University
• Principal Investigator: Osonoi Sho 弘前大学, 医学研究科, 客員研究員 (40816261)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 糖尿病性神経障害 / マクロファージ / 終末糖化産物 / RAGE / 軸索輸送

Outline of Final Research Achievements

Radical treatment for diabetic neuropathy (DPN) has not been established. In this study, we focused on the signaling of advanced glycation end products and their receptors, RAGE, and macrophage-mediated inflammation as pathological mechanisms for novel therapeutic targets. Diabetic RAGE-deficient mice and diabetic bone marrow cell-specific RAGE-deficient mice, which lack macrophage RAGE, showed reduced development and progression of DPN. Through detailed analysis, we elucidated the pathological mechanism by which activation of RAGE signaling induces macrophages infiltrating peripheral nerves to differentiate into pro-inflammatory phenotype and induces neuropathy through decreased insulin sensitivity of nerves by inflammatory cytokines and impaired axonal transport.

Free Research Field

糖尿病性合併症

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、マクロファージにおけるRAGEシグナルがDPNの発症・進展に関与し、その抑制がDPNの新規治療法となる可能性が示された。DPNは最も有病率が高く、早期に発症する糖尿病性合併症であり、進行期には下肢の壊疽や心臓血管自律神経障害の合併により予後を左右する。有効な治療法を開発することで患者のQOLや予後の改善、医療経済負担の削減が期待される。