Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells

IF 14.3 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Advanced Science Pub Date : 2024-07-31 DOI:10.1002/advs.202405325

Lu Zhang, Maoqing Tian, Meng Zhang, Chen Li, Xiaofei Wang, Yuyu Long, Yujuan Wang, Jijia Hu, Cheng Chen, Xinghua Chen, Wei Liang, Guohua Ding, Hua Gan, Lunzhi Liu, Huiming Wang

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Abstract

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.

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叉头盒蛋白 K1 通过驱动肾小管上皮细胞中的糖酵解促进慢性肾病的发生

在慢性肾脏病（CKD）进展过程中，肾小管上皮细胞（TECs）经历了从脂肪酸氧化到糖酵解的能量相关代谢转变。然而，这种糖酵解爆发的机制仍不清楚。本文报告了一种新的关键糖酵解调节因子--转录因子叉头盒蛋白 K1（FOXK1），它在肾脏纤维化过程中会在 TECs 中表达，并表现出纤维化和新陈代谢诱导能力。对 TECs 中 Foxk1 基因座的遗传修饰改变了糖酵解代谢和纤维化病变。FOXK1 蛋白激活后，一组糖酵解相关基因的表达激增，促成了与能量有关的代谢转变。核转移的 FOXK1 通过液-液相分离（LLPS）形成凝结物，驱动靶基因的转录。绘制并验证了 FOXK1 蛋白中的核心内在紊乱区域。通过肾囊下注射编码 Foxk1 短发夹 RNA 的重组腺相关病毒 9 载体，在 CKD 小鼠模型中靶向 Foxk1 基因座，探索了一种治疗策略。总之，FOXK1 介导的 TECs 糖酵解爆发机制已被阐明，该机制涉及 LLPS 以增强 FOXK1 的转录活性。

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

Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY

CiteScore

18.90

自引率

2.60%

发文量

1602

审稿时长

1.9 months

期刊介绍： Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.