Epithelial cells (ECs) have been proposed to contribute to myofibroblasts or fibroblasts through epithelial-mesenchymal transition (EMT) during renal fibrosis. However, since EMT may occur dynamically, transiently, and reversibly during kidney fibrosis, conventional lineage tracing based on Cre-loxP recombination in renal ECs could hardly capture the transient EMT activity, yielding inconsistent results. Moreover, previous EMT research has primarily focused on renal proximal tubule ECs, with few reports of distal tubules and collecting ducts. Here, we generated dual recombinases-mediated genetic lineage tracing systems for continuous monitoring of transient mesenchymal gene expression in E-cadherin⁺ and EpCAM⁺ ECs of distal tubules and collecting ducts during renal fibrosis. Activation of key EMT-inducing transcription factor (EMT-TF) Zeb1 and mesenchymal markers αSMA, vimentin, and N-cadherin, were investigated following unilateral ureteral obstruction (UUO). Our data revealed that E-cadherin⁺ and EpCAM⁺ ECs did not transdifferentiate into myofibroblasts, nor transiently expressed these mesenchymal genes during renal fibrosis. In contrast, in vitro a large amount of cultured renal ECs upregulated mesenchymal genes in response to TGF-β, a major inducer of EMT.

中文翻译：

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肾纤维化过程中远端肾小管和集合管上皮细胞瞬时间充质基因活性的连续遗传监测

上皮细胞（EC）被认为在肾纤维化过程中通过上皮-间质转化（EMT）促进肌成纤维细胞或成纤维细胞的形成。然而，由于EMT在肾纤维化过程中可能动态、短暂且可逆地发生，因此基于肾EC中Cre-loxP重组的传统谱系追踪很难捕获短暂的EMT活性，从而产生不一致的结果。此外，以往的EMT研究主要集中在肾近曲小管内皮细胞上，对远端肾小管和集合管的报道很少。在这里，我们生成了双重组酶介导的遗传谱系追踪系统，用于连续监测肾纤维化过程中远端肾小管和集合管的E-cadherin ⁺和 EpCAM ⁺ EC 中的瞬时间充质基因表达。在单侧输尿管梗阻 (UUO) 后研究了关键 EMT 诱导转录因子 (EMT-TF) Zeb1 和间充质标记物 αSMA、波形蛋白和 N-钙粘蛋白的激活。我们的数据显示，E-cadherin ⁺和 EpCAM ⁺ ECs 不会转分化为肌成纤维细胞，也不会在肾纤维化过程中短暂表达这些间质基因。相比之下，体外培养的大量肾内皮细胞响应 TGF-β（EMT 的主要诱导剂）而上调间充质基因。