Kha Michelle, Magnusson Ylva, Johansson Iva, Altiparmak Gülay, Lundgren Jaana, Nyström Jenny, Ebefors Kerstin, Swärd Karl, Johansson Martin E
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Am J Pathol. 2025 May;195(5):845-860. doi: 10.1016/j.ajpath.2025.01.011. Epub 2025 Feb 13.
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.
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（PTs）的上皮分化，并且对于维持成熟的PT表型至关重要。此外，在小鼠模型的肾损伤后观察到HNF4A下调。本研究的目的是调查HNF4A在急性和慢性人类肾脏疾病中的作用，以及在培养的PT细胞中成熟PT表型的丧失情况。免疫组织化学显示，在急性和慢性肾脏疾病期间，HNF4A表达的丧失和波形蛋白表达的增加是相互的且呈渐进性。健康人类肾脏在波形蛋白阳性的散在肾小管细胞中显示出HNF4A表达部分或完全丧失。PT细胞的原代细胞分离和传代培养重现了与HNF4A相关的PT表型丧失。如RNA测序和基因集富集分析所示，通过腺病毒转导在培养的PT细胞中重新表达HNF4A可增加与刷状缘形成以及吸收和转运过程相关的转录本。因此，HNF4A的减少和波形蛋白表达的增加与急性和慢性肾脏疾病均相关，并且代表了PT的一种刻板的损伤反应，导致去分化。在培养的原代PT细胞中重新表达HNF4A可为研究PT功能和损伤提供一个更可靠且可预测的体外模型。
