Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice

Noriyuki Yamashita, Tetsuro Kusaba, Tomohiro Nakata, Aya Tomita, Tomoharu Ida, Noriko Watanabe-Uehara, Kisho Ikeda, Takashi Kitani, Masahiro Uehara, Yuhei Kirita, Satoaki Matoba, Benjamin D. Humphreys, Keiichi Tamagaki

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)F579-F591
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number4
DOIs
StatePublished - Oct 2020

Keywords

  • Acute kidney injury
  • Epithelial-mesenchymal transition
  • Focal adhesion kinase
  • Renal tubular atrophy

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