Nakanoh Hiroyuki, Tsuji Kenji, Fukushima Kazuhiko, Haraguchi Soichiro, Kitamura Shinji, Wada Jun
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Nephrology, Aoe Clinic, Okayama, Japan.
Am J Nephrol. 2025 Feb 20:1-9. doi: 10.1159/000544795.
Acute kidney injury associated with the consumption of Beni-koji CholesteHelp supplements, which contain red yeast rice (Beni-Koji), has become a significant public health concern in Japan. While renal biopsy findings from several case reports have suggested tubular damage, no definitive causal relationship has been established, and the underlying mechanisms of kidney injury remain poorly understood. The complexity of identifying toxic substances in supplements containing various bioactive compounds makes conventional investigative approaches both time-consuming and challenging. This highlights an urgent need to establish a reliable platform for assessing organ-specific toxicity in such supplements. In this study, we utilized a kidney organoid model derived from adult rat kidney stem cells (KS cells) to assess the potential tubular toxicity of these supplements.
KS cell clusters were cultured in three-dimensional system supplemented with growth factors to promote kidney organoids. The organoids were subsequently exposed to Beni-koji CholesteHelp supplements or cisplatin, followed by histological and molecular analyses to evaluate structural impacts.
Established organoids had the kidney-like structures including tubular-like structures and glomerulus-like structures at the tips of multiple tubules. Treatment with Beni-koji CholesteHelp supplements induced significant tubular damage in the organoids, characterized by epithelial cell thinning, structural disruption, and increase in cleaved-caspase 3-positive apoptotic tubular cells, similar to the organoids treated with cisplatin.
These findings provide the first evidence suggesting that certain toxicants in specific batches of Beni-koji CholesteHelp supplements cause direct renal tubular injury. This KS cell-based organoid system represents a cost-effective, reproducible, and technically simple platform for nephrotoxicity screening.
食用含有红曲米（红曲）的Beni-koji CholesteHelp补充剂所导致的急性肾损伤，已成为日本一个重大的公共卫生问题。尽管一些病例报告中的肾活检结果提示存在肾小管损伤，但尚未确立明确的因果关系，肾损伤的潜在机制仍知之甚少。在含有各种生物活性化合物的补充剂中识别有毒物质的复杂性，使得传统的调查方法既耗时又具有挑战性。这凸显了迫切需要建立一个可靠的平台来评估此类补充剂中器官特异性毒性。在本研究中，我们利用源自成年大鼠肾干细胞（KS细胞）的肾类器官模型来评估这些补充剂的潜在肾小管毒性。
将KS细胞团在添加生长因子的三维系统中培养，以促进肾类器官的形成。随后将类器官暴露于Beni-koji CholesteHelp补充剂或顺铂中，接着进行组织学和分子分析以评估结构影响。
所建立的类器官具有类似肾脏的结构，包括在多个肾小管末端的管状结构和肾小球样结构。用Beni-koji CholesteHelp补充剂处理可导致类器官出现明显的肾小管损伤，其特征为上皮细胞变薄、结构破坏以及裂解的半胱天冬酶3阳性凋亡肾小管细胞增加，这与用顺铂处理的类器官相似。
这些发现提供了首个证据，表明特定批次的Beni-koji CholesteHelp补充剂中的某些有毒物质会导致直接的肾小管损伤。这种基于KS细胞的类器官系统代表了一种用于肾毒性筛查的经济高效、可重复且技术简单的平台。
