Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis.

中文翻译：

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精确切割肾脏切片作为人类肾纤维化治疗药物的体外筛选平台的预测价值。

动物模型是临床前研究中的宝贵工具。然而，传统模型中人类生物学反应的有限预测性刺激了人们对显示翻译鲁棒性的可靠临床前工具的追求。在这里，我们使用精密切肾切片（PCKS）作为肾纤维化的模型，并研究了其筛选抗纤维化药物的预测能力。鼠和人PCKS暴露于具有确定的抗纤维化功效的TGFβ或PDGF途径抑制剂。对于每种治疗方式，我们评估其是否影响：（1）培养物诱导的I型胶原基因表达和间质积累；（2）TGFβ和PDGF信号转导的标志物的表达；（3）炎症标志物的表达。我们总结了已发表的体内动物和人体研究结果，这些研究测试了三种抑制剂在肾纤维化中的作用，并得出了与PCKS数据相似的结果。我们表明，鼠类PCKS对抗纤维化的反应与在各种肾纤维化动物模型中观察到的已知体内反应高度一致。此外，我们的结果表明，人PCKS可用于预测临床试验中的药物疗效。总之，我们的研究表明PCKS​​模型是用于体外筛选肾纤维化推定药物的强大预测工具。我们的结果表明，人PCKS可用于预测临床试验中的药物疗效。总之，我们的研究表明PCKS​​模型是用于体外筛选肾纤维化推定药物的强大预测工具。我们的结果表明，人PCKS可用于预测临床试验中的药物疗效。总之，我们的研究表明PCKS​​模型是用于体外筛选肾纤维化推定药物的强大预测工具。