Predicting nucleic acid drug-induced nephrotoxicity using a 3D human renal proximal tubule spheroid model

DOI Web Site 参考文献36件
  • Morimura Kaoru
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd. Department of Systems Bioscience, Graduate School of Systems Life Sciences, Kyushu University
  • Takahashi Etsushi
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd.
  • Maeda Hayata
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd.
  • Nishioka Yukiko
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd.
  • Araki Ayano
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd.
  • Mizumoto Hiroshi
    Department of Systems Bioscience, Graduate School of Systems Life Sciences, Kyushu University
  • Jimbo Yoichi
    Bio Business Promotion Department, Medical Division, NIKKISO Co., Ltd.

書誌事項

公開日
2026
DOI
  • 10.2131/jts.51.75
公開者
一般社団法人　日本毒性学会

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説明

<p>Nucleic acid drugs hold considerable promise; however, their toxicological profiles are often difficult to assess in animal models. Clinical studies have reported adverse effects, including thrombocytopenia, complement activation, hepatotoxicity, and nephrotoxicity. While human cell-based models for hepatotoxicity are advancing, nephrotoxicity assessment remains limited by the scarcity of physiologically relevant kidney cells. In this study, a three-dimensional spheroid model of human primary renal proximal tubule epithelial cells (3D-RPTEC, Nikkiso) was employed to evaluate the nephrotoxicity of nucleic acid drugs. Proteomic profiling revealed enhanced expression of drug transporters and endocytic machinery in 3D-RPTEC compared with two-dimensional cultures. Lipofection enabled efficient intracellular delivery of nucleic acids. Toxicity was assessed using ATP quantification, biomarker analysis (LDH, KIM-1, NGAL), and high-content analysis (HCA). Significant ATP depletion was observed only after prolonged exposure to SPC5001, a nephrotoxic antisense oligonucleotide. In contrast, biomarker expression and HCA facilitated early detection of compound-specific toxicity and implicated endoplasmic reticulum and mitochondrial stress as underlying mechanisms. These findings establish 3D-RPTEC as a sensitive and physiologically relevant platform for predicting the nephrotoxic potential of nucleic acid drugs.</p>

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