Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells
Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells
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DOI：
10.1021/mp400637s
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发表时间：
2014-07-01
影响因子：
4.9
通讯作者：
Zink, Daniele
中科院分区：
文献类型：
--
作者：
Li, Yao;Kandasamy, Karthikeyan;Zink, Daniele
肾脏是药物引起的毒性的主要靶标，肾近曲小管经常受到影响。肾毒性通常仅在药物开发后期才被检测到，并且新批准药物的肾毒性潜力往往被低估。一个核心问题是缺乏具有高预测性的临床前模型。目前尚无用于预测肾毒性的经过验证的体外模型。主要问题与适当细胞模型和终点的识别有关。由于药物引起的肾损伤与炎症反应相关，因此我们探讨了炎症标志物的表达作为肾体外模型的终点。与此同时，我们开发了一种新的细胞模型。在这里，我们结合这些方法，开发了一种使用胚胎干细胞衍生的人肾近端肾小管样细胞的体外模型，该模型使用白细胞介素 (IL)-6 和 IL-8 的表达作为终点。该模型的预测能力通过 41 种特征明确的化合物进行了评估。结果表明，该模型可以高精度预测人类近端肾小管毒性。相反，当使用完善的标准体外测定时，预测率较低。总之，结果表明，使用多能斯坦细胞衍生的人肾近端肾小管样细胞的体外模型可以获得高预测性。
The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stein cell-derived human renal proximal tubular-like cells.