Transcriptional regulatory systems controlling renal tubular endocytosis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07861
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Harita Yutaka 東京大学, 医学部附属病院, 准教授 (10451866)
• Co-Investigator(Kenkyū-buntansha): 神田 祥一郎 東京大学, 医学部附属病院, 講師 (60632651)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腎尿細管 / エンドサイトーシス / Fanconi症候群

Outline of Final Research Achievements

Disrupted reabsorption in the renal proximal tubules leads to Fanconi syndrome. Mutations in HNF4A, which encodes the transcription factor HNF4α, cause juvenile-onset adult-onset diabetes mellitus. Noticeably, HNF4A R76W mutation, unlike other HNF4A mutations, causes Fanconi syndrome. This study aims to clarify its downstream and to elucidate the molecular network involved in tubular reabsorption.
Using a cultured cell model, we identified molecules whose transcription is promoted by HNF4A and further altered by R76W mutation. Of those identified, we focused on candidate factor X, whose function is unknown. We generated knockout mice for X and found that heterozygous knockout mice had no phenotype. The homozygous knockout mice exhibited Fanconi syndrome, indicating that X has an essential function in the kidney. RNA-seq and renal tissue staining of renal tissue revealed variable expression of several molecules associated with endocytosis in the tubules.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

腎臓は血液をろ過して老廃物を除去する重要な器官です。尿細管とよばれる管では一度尿にろ過された物質を再吸収・再利用するプロセスが行われており、エンドサイトーシスと呼ばれます。体内の物質バランスを維持する上で不可欠な機能のため、その異常は、さまざまな腎疾患の発症に関与することが知られています。
本研究は遺伝子異常で起こる腎尿細管エンドサイトーシスの異常に着目し、そのメカニズムを明らかにすることを目的にしています。
腎尿細管の再吸収機構の理解は、腎臓病の予防や治療法の開発に重要な知見の基盤となると考えられます。