肾毒性评价体外替代模型研究进展

Progress in researches on in vitro alternative model for nephrotoxicity evaluation

随着《21世纪毒性测试:愿景与策略》的提出,毒性测试的重点开始从整体动物实验转向基于人类细胞或细胞组分等替代方法的测试策略。由于肾毒性物质的靶器官选择性,且药物诱导的肾损伤是新药开发时需解决的重要问题,故需良好的体外替代模型来评价包括药物在内的外源性化合物的肾脏毒性。然而,现有的体外模型由于缺少肾小管上皮细胞在体内的形态及功能,难以预测外源性化合物的肾脏毒性。肾体外替代模型的细胞来源、特点、培养条件以及检测终点是在建立体外替代模型时重点考虑的问题。多功能干细胞诱导分化肾细胞的出现、3D培养及肾脏芯片技术的发展、组学技术、高内涵筛选的应用为体外模型的建立及模型预测结果从体外到体内的外推提供了新思路。

With the introduction of Toxicity Testing in the 21st Century:A Vision and Strategy,the focus of toxicity testing has shifted from animal experiments to in vitro models using human resource cells or cellular components.As kidney is a major target for drug-induced toxicity and the drug-induced toxicity remains a major problem in developing new drugs,a predictive in vitro model is urgently needed to evaluate the renal toxicity of exogenous compounds.However,current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to that would be nephrotoxic in vivo.The resource and characteristics of cellular models,cell culture conditions,and readouts of injury are important in establishing an in vitro model.The development of differentiation of pluripotent stem cells into multiple renal cell types,3 dimensional culture systems and kidney-on-a-chip technology,omics technology and high-content screening have opened a range of potential new platforms for evaluating compounds nephrotoxicity and promoted in vitro to in vivo extrapolation.This study summarizes the latest advances in in vitro nephrotoxicity assessment models.