Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Am J Physiol Renal Physiol. 2020 Oct 1;319(4):F579-F591. doi: 10.1152/ajprenal.00108.2020. Epub 2020 Aug 17.
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 nonfunctional tubules, and FAK inhibition was sufficient to prevent tubular atrophy. In vitro, transforming growth factor-β induced FAK phosphorylation and an EMT phenotype, which was also prevented by FAK inhibition. In an in vitro tubular epithelia gel contraction assay, transforming growth factor-β 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.
管状萎缩是肾脏纤维化的一种常见病理特征。虽然成纤维细胞在组织纤维化中起主要作用，但修复管状上皮在管状萎缩中的作用尚不清楚。我们证明了在严重缺血再灌注损伤（IRI）后，局灶黏附激酶（FAK）介导的管内上皮-间充质转化（EMT）在管状萎缩发病机制中的重要作用。在严重 IRI 的急性期，观察到活跃增殖的管状上皮经历管内 EMT，导致慢性期的管状萎缩，反映出管状修复失败。此外，在严重 IRI 的急性期，FAK 在管状上皮中磷酸化，其抑制作用改善了损伤后慢性期的管状萎缩和间质纤维化。在使用近端小管报告小鼠对 IRI 后的单个标记近端肾小管上皮细胞进行体内克隆分析后，IRI 后发现大量克隆扩张，反映了修复过程中的上皮活跃增殖。这些增殖的上皮大多数位于萎缩和无功能的小管中，FAK 抑制足以预防管状萎缩。在体外，转化生长因子-β诱导 FAK 磷酸化和 EMT 表型，这也可以被 FAK 抑制所预防。在体外管状上皮凝胶收缩测定中，转化生长因子-β处理加速了凝胶收缩，这可以被 FAK 抑制所抑制。总之，损伤诱导的管内 EMT 与 FAK 依赖性管状萎缩密切相关。
