Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Nat Rev Nephrol. 2018 Jun;14(6):378-393. doi: 10.1038/s41581-018-0003-9.
In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.
目前，体外筛选对肾毒性的预测效果不佳。尽管表达于肾单位小管的功能蛋白及其介导的药物易感性已广为人知，但目前的体外细胞模型在形态和功能上都不能很好地复制肾小管，因此无法证明对体内具有肾毒性的药物的损伤反应。用于指导多能干细胞向多种肾细胞类型分化的方案的进步，以及微流控和 3D 培养系统的发展，为评估药物肾毒性开辟了一系列潜在的新平台。许多新的体外培养系统的特点是表达和功能转运蛋白、酶和其他由肾脏表达并与药物诱导的肾损伤有关的功能蛋白。表达这些蛋白并表现出作为损伤生物标志物的分子标志物的体外平台与静态 2D 培养相比，表现出更好的功能成熟度，为迄今受到较少关注的肾细胞类型的损伤建模提供了机会。随着肾毒性筛选平台变得更加具有生理相关性，它们将有助于开发更安全的药物和改善对肾毒物的临床管理。
