Institute of Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Dusseldorf, Germany.
Cells. 2022 Feb 11;11(4):635. doi: 10.3390/cells11040635.
Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic options are urgently needed. Within the kidney, the glomeruli are involved in blood filtration and waste excretion and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be employed to induce acute glomerular damage and to model glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations revealed the disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell-death-related processes. We conclude that the treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated by an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine-stem-cell-derived kidney organoids can be used to model kidney-associated diseases and drug discovery.
肾脏疾病，包括急性肾损伤（AKI）和慢性肾脏病（CKD），可进展为终末期肾病（ESRD），是全球范围内的健康负担。器官移植或肾脏透析是唯一有效的治疗手段。因此，迫切需要肾脏疾病的体外模型和潜在治疗方法的开发。在肾脏中，肾小球参与血液过滤和废物排泄，很容易受到细胞状态变化的影响。嘌呤霉素氨基核苷（PAN）是一种肾毒素，可用于诱导急性肾小球损伤和肾小球疾病模型。基于此，我们从三个 iPSC 系中生成了肾脏类器官，并对其进行 PAN 处理以诱导肾脏损伤。形态学观察显示，PAN 处理后肾脏类器官中的肾小球和肾小管结构遭到破坏，转录组分析也证实了这一点。随后的分析显示，免疫反应以及炎症和细胞死亡相关过程上调。我们的结论是，用 PAN 处理 iPSC 衍生的肾脏类器官会引发炎症、细胞骨架重排、DNA 损伤、细胞凋亡和细胞死亡相互交织的网络介导的肾脏损伤。此外，尿干细胞衍生的肾脏类器官可用于肾脏相关疾病的建模和药物发现。
