Retinoic acid-deficient renal mesangial cells are responsible for the development of diabetic nephropathy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08697
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Osanai Makoto 札幌医科大学, 医学部, 教授 (60381266)
• Co-Investigator(Kenkyū-buntansha): 澤田 典均 札幌医科大学, 医学部, 名誉教授 (30154149)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ビタミンA / レチノイン酸 / レチノイン酸代謝酵素CYP26 / 星細胞 / 腎メサンギウム細胞 / 糖尿病 / 糖尿病性腎症 / 腎不全

Outline of Final Research Achievements

Diabetic nephropathy is the greatest single cause of hemodialysis due to renal failure. Here we propose that glomerular endothelial tight junctions (TJs) are plausible therapeutic targets for diabetic nephropathy because TJs primarily determine the vascular permeability. Indeed, mesangial cell-derived cytokines limit vascular leakiness of capillaries and eventually attenuate the breakdown of vascular integrity in diabetic angiopathy. We found that CYP26A1, an enzyme specifically involved in metabolic inactivation of retinoic acid (RA), is highly expressed in diabetic glomeruli. We also found that the state of reduced RA bioavailability caused by enhanced expression of CYP26A1 is sufficient to increase vascular permeability and causally leads to glomerular fibrosis and sclerosis. Our observations provide substantial evidence for deteriorating factor of CYP26A1 in diabetic angiopathy, and suggest mechanisms whereby RA deficient-mesangial cells might promote diabetic nephropathy.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

星細胞は，ユニークな機能的特徴を有するが，これまで，いわば脇役であった．しかし，さまざまな疾患病態を直接制御する主役の可能性がある．レチノイン酸を用いて，星細胞を起点に腎糸球体の機能異常を理解する試みは，これまで類をみない．また，星細胞を中心とする機能ユニット全体を薬理学的に制御する戦略は，チャレンジ性の高い研究プロジェクトである．星細胞を標的とし，糖尿病性腎症を治療または予防する戦略は，きわめて独創的であり，臨床的に重要である．事実，全透析患者の40%以上は，糖尿病性腎症が原因である．透析を導入する基礎疾患として最も多く，疾患の発症を制御する戦略の創出は，社会的に急務である．