Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells

PLoS One. 2016 May 19;11(5):e0154912. doi: 10.1371/journal.pone.0154912. eCollection 2016.

Abstract

Tubular epithelial cells (TECs) can be dedifferentiated by repetitive insults, which activate scar-producing cells generated from interstitial cells such as fibroblasts, leading to the accumulation and deposition of extracellular matrix molecules. The dedifferentiated TECs play a crucial role in the development of renal fibrosis. Therefore, renal fibrosis may be attenuated if dedifferentiated TECs are converted back to their normal state (re-epithelialization). However, the mechanism underlying the re-epithelialization remains to be elucidated. In the present study, TGF-β1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-β1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1β) was identified as a candidate molecule involved in inducing re-epithelialization by means of DNA microarray and biological network analysis. In functional validation studies, the re-epithelialization by TGF-β1 removal was abolished by HNF-1β knockdown. Furthermore, the ectopic expression of HNF-1β in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-β/Smad signaling, even in the presence of TGF-β1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1β expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1β downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1β suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1β in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Cell Dedifferentiation*
  • Cell Differentiation*
  • Cytokines / metabolism
  • Epithelial Cells / cytology*
  • Female
  • Fibrosis / metabolism
  • Gene Expression Profiling
  • Hepatocyte Nuclear Factor 1-beta / metabolism*
  • Humans
  • Immunohistochemistry
  • Kidney / pathology
  • Kidney Tubules / cytology
  • Mice
  • Mice, Inbred ICR
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Smad Proteins / metabolism

Substances

  • Cytokines
  • HNF1B protein, human
  • Hnf1b protein, mouse
  • RNA, Small Interfering
  • Smad Proteins
  • Hepatocyte Nuclear Factor 1-beta

Grants and funding

All authors are employed by a commercial company, Asubio Pharma Co., Ltd. The authors include the following statement: The funder provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.