Tubular atrophy is a common pathological feature of kidney fibrosis. Although fibroblasts play a predominant role in tissue fibrosis, the role of repairing tubular epithelia in tubular atrophy is unclear. We demonstrated the essential role of focal adhesion kinase (FAK)-mediated intratubular epithelial-mesenchymal transition (EMT) in the pathogenesis of tubular atrophy after severe ischemia-reperfusion injury (IRI). Actively proliferating tubular epithelia undergoing intratubular EMT were noted in the acute phase of severe IRI, resulting in tubular atrophy in the chronic phase, reflecting failed tubular repair. Furthermore, FAK was phosphorylated in the tubular epithelia in the acute phase of severe IRI, and its inhibition ameliorated both tubular atrophy and interstitial fibrosis in the chronic phase after injury. In vivo clonal analysis of single-labeled proximal tubular epithelial cells after IRI using proximal tubule reporter mice revealed substantial clonal expansion after IRI, reflecting active epithelial proliferation during repair. The majority of these proliferating epithelia were located in atrophic and non-functional tubules, and FAK inhibition was sufficient to prevent tubular atrophy. In vitro, TGFβ induced FAK phosphorylation and an EMT phenotype, which was also prevented by FAK inhibition. In an in vitro tubular epithelia gel contraction assay, TGFβ treatment accelerated gel contraction, which was suppressed by FAK inhibition. In conclusion, injury-induced intratubular EMT is closely related to tubular atrophy in a FAK-dependent manner.

中文翻译：

---

小鼠肾脏损伤后肾小管上皮间质转化和肾小管萎缩。

肾小管萎缩是肾纤维化的常见病理特征。尽管成纤维细胞在组织纤维化中起主要作用，但在肾小管萎缩中修复肾小管上皮的作用尚不清楚。我们证明了在严重缺血再灌注损伤（IRI）后肾小管萎缩的发病机理中，粘着斑激酶（FAK）介导的肾小管上皮间质转化（EMT）的重要作用。在严重IRI的急性期注意到活跃的肾小管上皮细胞正在经历小管内EMT，在慢性期导致肾小管萎缩，反映出肾小管修复失败。此外，FAK在严重IRI急性期的肾小管上皮中被磷酸化，其抑制作用在损伤后的慢性期改善了肾小管萎缩和间质纤维化。使用近端肾小管报告基因小鼠的IRI后单标记的近端肾小管上皮细胞的体内克隆分析显示IRI后实质性的克隆扩增，反映了修复过程中活跃的上皮增殖。这些增生的上皮细胞大多数位于萎缩和无功能的小管中，FAK抑制作用足以防止肾小管萎缩。在体外，TGFβ诱导FAK磷酸化和EMT表型，这也被FAK抑制所阻止。在体外肾小管上皮凝胶收缩试验中，TGFβ处理可加速凝胶收缩，而FAK抑制可抑制这种收缩。总之，损伤诱导的肾小管内EMT以FAK依赖性方式与肾小管萎缩密切相关。