肾脏器官样本是研究肾脏疾病的一种有希望的模型，但由于对它们的功能性蛋白质表达谱的知识有限，它们的使用受到局限。本研究在此中定义了器官样本的蛋白质组和转录组的变化轨迹，包括在培养期间和暴露于细胞因子应激物TNFα后的变化。老化的器官样本增加了细胞外基质的沉积，但减少了肾小球蛋白的表达。单细胞转录组整合显示大部分蛋白组变化发生在足细胞、小管细胞和间质细胞中。器官样本暴露于TNFα后，322种差异表达的蛋白质被发现，其中包括细胞因子和补体成分。这322种蛋白质的转录表达在蛋白尿性肾脏疾病患者中明显升高，且其临床结果较差。TNFα相关蛋白质（C3和VCAM1）的表达在人类肾小管和器官样本肾细胞中均升高，突显了器官样本在生物标志物开发方面的潜力。通过整合肾脏器官样本组学层，并结合与人类数据的对比，将相关疾病的细胞因子应激物纳入其中，我们为肾脏器官样本模型与人类肾脏疾病的功能相关性提供了重要证据。© 2023 Springer Nature Limited.

Kidney organoids are a promising model to study kidney disease, but their use is constrained by limited knowledge of their functional protein expression profile. Here, we define the organoid proteome and transcriptome trajectories over culture duration and upon exposure to TNFα, a cytokine stressor. Older organoids increase deposition of extracellular matrix but decrease expression of glomerular proteins. Single cell transcriptome integration reveals that most proteome changes localize to podocytes, tubular and stromal cells. TNFα treatment of organoids results in 322 differentially expressed proteins, including cytokines and complement components. Transcript expression of these 322 proteins is significantly higher in individuals with poorer clinical outcomes in proteinuric kidney disease. Key TNFα-associated protein (C3 and VCAM1) expression is increased in both human tubular and organoid kidney cell populations, highlighting the potential for organoids to advance biomarker development. By integrating kidney organoid omic layers, incorporating a disease-relevant cytokine stressor and comparing with human data, we provide crucial evidence for the functional relevance of the kidney organoid model to human kidney disease.© 2023. Springer Nature Limited.