Elucidation of the non-immunological mechanism of chronic allograft nephropathy for long-term engraftment and development of prevention methods

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K09738
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Keio University
• Principal Investigator: Morita Shinya 慶應義塾大学, 医学部(信濃町), 助教 (10365364)
• Co-Investigator(Kenkyū-buntansha): 篠田 和伸 慶應義塾大学, 医学部(信濃町), 講師 (60348737) ; 環 聡 慶應義塾大学, 医学部(信濃町), 訪問研究員 (20626741) ; 吉田 理 慶應義塾大学, 医学部(信濃町), 准教授 (00306713) ; 高橋 遼平 慶應義塾大学, 医学部(信濃町), 訪問研究員 (90815367)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: シクロスポリン腎症 / NF-κB / DHMEQ / 慢性移植腎症

Outline of Final Research Achievements

We created rat models of Cyclosporine A (CsA) nephrotoxicity and rat models which was administered Nuclear factor-κB (NF-κB)inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ).We showed that DHMEQ inhibited NF-κB activation and contributed to the protection of the kidney against functional and histopathological damages in this model. One of the mechanisms is an indirect effect of DHMEQ that reduces MCP-1 secretion. MCP-1 is one of the major mediators of chemotaxis and macrophage activation. Another mechanism is a direct effect of DHMEQ that inhibits macrophage activation and phagocytosis. DHMEQ treatment did not offset the inhibitory effect of urinary protein extraction due to CsA.

Free Research Field

腎移植

Academic Significance and Societal Importance of the Research Achievements

増加し続ける慢性腎不全患者に対する治療のうち、予後およびQOLの改善、さらに医療経済の点で透析に勝る腎移植の長期生着を阻む原因が慢性移植腎症(choronic/sclerosing allograft nephropathy:CAN)である。CANの原因の一因といわれるシクロスポリン(CsA)腎症における研究で、DHMEQ(dehydroxymethylepoxyquinomicin）がCsA投与ラットの腎臓でNF-κB活性化を抑制し、機能的、組織学的障害を軽減することが示された。免疫抑制効果もあるDHMEQが、臓器移植でのCsA腎症の抑制ひいてはCAN克服につながる可能性を示すことができた。