Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice
Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice
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DOI：
10.1152/ajprenal.00108.2020
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发表时间：
2020-10-01
影响因子：
4.2
通讯作者：
Tamagaki, Keiichi
中科院分区：
文献类型：
--
作者：
Yamashita, Noriyuki;Kusaba, Tetsuro;Tamagaki, Keiichi
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，但修复肾小管上皮细胞在肾小管萎缩中的作用尚不清楚。我们证实了粘着斑激酶(FAK)介导的肾小管上皮-间充质转化(EMT)在严重缺血再灌注损伤(IRI)后肾小管萎缩的发病机制中的重要作用。在严重IRI的急性期，行肾小管内EMT的肾小管上皮细胞增殖活跃，导致慢性期肾小管萎缩，反映肾小管修复失败。此外，FAK在重度IRI急性期肾小管上皮细胞中被磷酸化，其抑制作用可减轻损伤后慢性期肾小管萎缩和间质纤维化。用近端小管报告鼠对IRI后单个标记的近端肾小管上皮细胞进行体内克隆性分析显示，IRI后大量克隆性扩张，反映修复过程中活跃的上皮细胞增殖。这些增殖的上皮细胞大多位于萎缩的和无功能的小管上皮细胞，抑制FAK足以防止肾小管萎缩。在体外，转化生长因子-β诱导FAK磷酸化和EMT表型，这也被FAK抑制所阻止。在体外肾小管上皮细胞凝胶收缩实验中，转化生长因子-β处理加速了凝胶收缩，而FAK抑制抑制了凝胶收缩。综上所述，损伤诱导的肾小管内EMT与肾小管萎缩密切相关，这种关系依赖于FAK。
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-beta 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-beta 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.