APOL1 risk variants induce metabolic reprogramming of podocytes in patient-derived kidney organoids.

IF 5.1 2区医学 Q1 CELL & TISSUE ENGINEERING

Stem Cell Reports Pub Date : 2025-10-02 DOI:10.1016/j.stemcr.2025.102650

Heein Song, Sébastien J Dumas, Gangqi Wang, Lijun Ma, Franca Witjas, M Cristina Avramut, Cathelijne W van den Berg, Michael V Rocco, Barry I Freedman, Ton J Rabelink, H Siebe Spijker

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Abstract

Carriers of two apolipoprotein L1 gene risk variants (RVs), termed G1 and G2, are at increased risk for chronic kidney disease. This study utilized induced pluripotent stem cells (iPSCs) derived from two patients homozygous for G1 and G2 to model human apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD) in kidney organoids. Single-cell transcriptomic analysis and immunofluorescence imaging showed APOL1 upregulation in podocytes after interferon-gamma (IFN-γ) treatment. Transcriptomics and spatial dynamic metabolomics demonstrated a significant reduction in oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity, along with upregulation of glycolysis and hypoxia signaling in RV podocytes. Isolated RV glomeruli exhibited no increase in maximal respiration rate following IFN-γ treatment, while iPSC-derived RV podocytes displayed a reduced number of mitochondrial branches and shorter branch length. This model presents early metabolic reprogramming of RV podocytes upon inflammatory injury and compelling evidence that mitochondrial dysfunction plays a pivotal role in the early pathophysiology of AMKD.

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APOL1风险变异诱导患者源性肾类器官足细胞代谢重编程。

两种载脂蛋白L1基因风险变异（RVs）的携带者，称为G1和G2，患慢性肾脏疾病的风险增加。本研究利用来自两名G1和G2纯合子患者的诱导多能干细胞（iPSCs）来模拟肾类器官中人载脂蛋白L1 （APOL1）介导的肾脏疾病（AMKD）。单细胞转录组学分析和免疫荧光成像显示干扰素-γ (IFN-γ)治疗后足细胞中APOL1上调。转录组学和空间动态代谢组学表明，RV足细胞的氧化磷酸化和三羧酸（TCA）循环活性显著降低，糖酵解和缺氧信号通路上调。IFN-γ处理后，离体RV肾小球的最大呼吸速率没有增加，而ipsc衍生的RV足细胞线粒体分支数量减少，分支长度缩短。该模型显示了炎症损伤后RV足细胞的早期代谢重编程，并有力地证明了线粒体功能障碍在AMKD的早期病理生理中起着关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY

CiteScore

10.50

自引率

1.70%

发文量

200

审稿时长

28 weeks

期刊介绍： Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.