紅麹コレステヘルプ腎症の原因物質と発症機序を解明～プベルル酸が引き起こすミトコンドリア障害を分子レベルで実証～

2026-03-03

2026-03-02 東京科学大学

東京科学大学の研究チームは、紅麹コレステヘルプ腎症の原因物質とされるプベルル酸の発症機序を解明した。マウスモデル、ヒト腎由来初代培養細胞、3次元培養尿細管オルガノイドを用いた解析の結果、有害ロット製品とプベルル酸投与で生じる腎障害がRNA発現レベルで高度に類似することを確認した。さらに、細胞死に先行してミトコンドリア膜電位低下、ATP減少、活性酸素種増加、呼吸鎖機能低下が起こることを実証し、ミトコンドリア障害が尿細管上皮細胞の壊死を引き起こす主要因であると示した。本成果は、原因不明だったコレステヘルプ腎症の分子機序に科学的根拠を与え、予後評価や治療法開発への基盤となる。

＊紅麹コレステヘルプとは、2024年3月に健康被害が報告され自主回収となった、小林製薬が販売していた機能性表示食品のサプリメントです。（Tii）

図1．マウスモデル病理画像（上:HE染色　下:PAS染色）

＜関連情報＞

紅麹コレステロール低下作用またはプベルラ酸誘発性腎障害の病態生理学的メカニズム The Pathophysiological Mechanism of Beni-koji Choleste-Help or Puberulic Acid–Induced Kidney Injury

Yuta Sekiguchi ∙ Makiko Mori ∙ Haruka Maruyama ∙ … ∙ Eisei Sohara ∙ Shinichi Uchida ∙ Yutaro Mori
Kidney International Reports Published:January 23, 2026
DOI:https://doi.org/10.1016/j.ekir.2026.103793

Abstract

Introduction

In March 2024, kidney injury caused by some specific red yeast rice supplements was reported in Japan. By November 2024, 2628 people had visited medical facilities, making it a social problem. Many patients still show decreased estimated glomerular filtration rate. Puberulic acid was reported to be present in Beni-koji Choleste-Help toxic lots. However, the pathophysiology is not yet clarified. Here, we discovered that mitochondrial dysfunction in renal proximal tubular epithelial cells is associated with, and may contribute to, nephrotoxicity.

Methods

To assess the effects of Beni-koji Choleste-Help toxic lots and puberulic acid, we performed RNA sequencing (RNA-seq), extracellular flux analysis, and other assays across multiple models, including human kidney biopsy specimens, primary human renal proximal tubular epithelial cells (hRPTECs), human renal organoids, and mice.

Results

A patient renal biopsy sample showed kidney injury molecule-1 expression in proximal tubules surrounded by activated myofibroblasts, indicating tubular damage and fibrosis. Mice treated with toxic lots and puberulic acid showed kidney injury with some features of Fanconi syndrome. Pathological sections revealed tubular necrosis and fibrosis. RNA-seq analysis of whole kidneys showed that the toxic lot and puberulic acid produced similar RNA patterns, suggesting puberulic acid is a causative agent. Gene ontology (GO) analysis comparing the normal and toxic lot revealed mitochondrial pathways downregulation. Puberulic acid showed toxicity to hRPTECs and tubular organoids. In vitro experiment revealed that it causes mitochondrial damage, especially to the respiratory metabolism, associated with subsequent cell death.