受伤的近端小管上皮细胞失去对刷状边界形成和运输至关重要的HNF4A表达。

IF 4.7 2区 医学 Q1 PATHOLOGY
Michelle Kha , Ylva Magnusson , Iva Johansson , Gülay Altiparmak , Jaana Lundgren , Jenny Nyström , Kerstin Ebefors , Karl Swärd , Martin E. Johansson
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引用次数: 0

摘要

最近的研究表明,转录因子肝细胞核因子4α (HNF4A)驱动肾近端小管(PT)的上皮分化,并对维持成熟的PT表型至关重要。此外,在小鼠肾损伤模型中观察到HNF4A下调。本研究的目的是研究HNF4A在急性和慢性人类肾脏疾病中的作用,以及培养的PT细胞中成熟PT表型的丧失。通过免疫组化,我们发现在急性和慢性肾脏疾病中HNF4A表达的丧失和vimentin表达的增加是相互的和渐进的。健康的人肾脏在vimentin阳性的散在小管细胞中显示HNF4A的部分或全部表达缺失。PT细胞的原代分离和传代培养再现了hnf4a相关的PT表型缺失。RNA测序和基因集富集分析显示,通过腺病毒转导在培养的PT细胞中重新表达HNF4A增加了与刷状边界形成以及吸收和运输过程相关的转录本。因此,HNF4A的减少和vimentin表达的增加与急性和慢性肾脏疾病有关,代表了PT的刻板损伤反应,导致去分化。HNF4A在培养的原代PT细胞中的再表达可以为研究PT功能和损伤提供更可靠和预测性的体外模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Injured Proximal Tubular Epithelial Cells Lose Hepatocyte Nuclear Factor 4α Expression Crucial for Brush Border Formation and Transport

Injured Proximal Tubular Epithelial Cells Lose Hepatocyte Nuclear Factor 4α Expression Crucial for Brush Border Formation and Transport
Recent studies have demonstrated that the transcription factor hepatocyte nuclear factor 4α (HNF4A) drives epithelial differentiation in the renal proximal tubules (PTs) and is critical for maintaining a mature PT phenotype. Furthermore, HNF4A down-regulation has been observed following kidney injury in mouse models. The aim of the present work was to investigate the role of HNF4A during acute and chronic human kidney disease and the loss of the mature PT phenotype in cultured PT cells. Loss of HNF4A expression and gain of vimentin expression were reciprocal and gradual during both acute and chronic kidney disease, as indicated by immunohistochemistry. Healthy human kidneys demonstrated partial or total loss of HNF4A expression in vimentin-positive scattered tubular cells. Primary cell isolation and subculture of PT cells recapitulated HNF4A-associated loss of the PT phenotype. Re-expression of HNF4A in cultured PT cells by adenoviral transduction increased transcripts related to brush border formation as well as absorptive and transport processes, as shown by RNA sequencing and gene set enrichment analyses. Thus, the reduction of HNF4A and increase of vimentin expression were connected to both acute and chronic kidney disease and represented a stereotypic injury response of the PT, resulting in dedifferentiation. HNF4A re-expression in cultured primary PT cells could provide a more reliable and predictive in vitro model to study PT function and injury.
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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