Pathophysiology of obesity related glomerulopathy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08218
• 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: Keio University
• Principal Investigator: TOKUYAMA HIROBUMI 慶應義塾大学, 医学部(信濃町), 講師 (50276250)
• Co-Investigator(Kenkyū-buntansha): 脇野 修 慶應義塾大学, 医学部(信濃町), 准教授 (50265823)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肥満関連腎症 / オートファジー / 腎虚血 / 低酸素 / ライソゾーム / リン脂質 / 尿細管 / phd

Outline of Final Research Achievements

High fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In addition, lysosomal storage disorders were observed in the early stage and autophagy related genes were changed. We created tamoxifen-inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and fed HFD or LFD. HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of lysosomal storage disorders in proximal tubules, proximal tubular damages, albuminuria and glomerulomegaly. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both lysosomal storage disorders and tubular damages in HFD-induced obese mice. An early intervention targeting PHD2 may represent a novel therapeutic strategy against obesity-induced kidney injury.

Free Research Field

肥満関連腎症

Academic Significance and Societal Importance of the Research Achievements

主要な末期腎不全原因疾患である糖尿病性腎症への治療介入として、これまで食事療法、レニン・アンジテンシン系抑制を中心とした降圧療法、血糖管理など多面的治療が行われてきた。しかし、腎症の進行・新規透析導入を抑制しきれておらず、病勢の進行阻止は喫緊の課題である。本研究は、糖尿病性腎症の前段階である肥満関連腎症の病態生理を明らかにするものであり、特に肥満関連腎症の超早期におけるオートファジー制御異常を初めて明らかにし、PHD/HIF経路とオートファジー制御異常の相関を明確にした。この新知見を応用し、PHD/HIF経路への治療介入による肥満関連腎症、糖尿病性腎症の進行抑止を目指すものである。