Drug-Induced Nephrotoxicity Assessment in 3D Cellular Models.

The kidneys are often involved in adverse effects and toxicity caused by exposure to foreign compounds, chemicals, and drugs. Early predictions of these influences are essential to facilitate new, safe drugs to enter the market. However, in current drug treatments, drug-induced nephrotoxicity accounts for 1/4 of reported serious adverse reactions, and 1/3 of them are attributable to antibiotics. Drug-induced nephrotoxicity is driven by multiple mechanisms, including altered glomerular hemodynamics, renal tubular cytotoxicity, inflammation, crystal nephropathy, and thrombotic microangiopathy. Although the functional proteins expressed by renal tubules that mediate drug sensitivity are well known, current in vitro 2D cell models do not faithfully replicate the morphology and intact renal tubule function, and therefore, they do not replicate in vivo nephrotoxicity. The kidney is delicate and complex, consisting of a filter unit and a tubular part, which together contain more than 20 different cell types. The tubular epithelium is highly polarized, and maintaining cellular polarity is essential for the optimal function and response to environmental signals. Cell polarity depends on the communication between cells, including paracrine and autocrine signals, as well as biomechanical and chemotaxis processes. These processes affect kidney cell proliferation, migration, and differentiation. For drug disposal research, the microenvironment is essential for predicting toxic reactions. This article reviews the mechanism of drug-induced kidney injury, the types of nephrotoxicity models (in vivo and in vitro models), and the research progress related to drug-induced nephrotoxicity in three-dimensional (3D) cellular culture models.

肾脏常常受到外来化合物、化学物质和药物暴露所导致的不良反应和毒性的影响。对这些影响进行早期预测对于促进新型安全药物进入市场至关重要。然而，在当前的药物治疗中，药物诱导的肾毒性占所报告的严重不良反应的四分之一，其中三分之一可归因于抗生素。药物诱导的肾毒性由多种机制驱动，包括肾小球血流动力学改变、肾小管细胞毒性、炎症、结晶性肾病和血栓性微血管病。尽管肾小管表达的介导药物敏感性的功能蛋白已广为人知，但目前的体外二维细胞模型不能如实复制肾小管的形态和完整功能，因此无法复制体内肾毒性。肾脏精细而复杂，由一个滤过单位和一个肾小管部分组成，它们总共包含20多种不同的细胞类型。肾小管上皮细胞高度极化，维持细胞极性对于最佳功能以及对环境信号的反应至关重要。细胞极性取决于细胞之间的通讯，包括旁分泌和自分泌信号，以及生物力学和趋化过程。这些过程影响肾细胞的增殖、迁移和分化。对于药物处置研究而言，微环境对于预测毒性反应至关重要。本文综述了药物诱导的肾损伤机制、肾毒性模型的类型（体内和体外模型）以及三维细胞培养模型中与药物诱导的肾毒性相关的研究进展。