Hnf-1β transcription factor is an early hif-1α-independent marker of epithelial hypoxia and controls renal repair

PLoS One. 2013 May 21;8(5):e63585. doi: 10.1371/journal.pone.0063585. Print 2013.


Epithelial repair following acute kidney injury (AKI) requires epithelial-mesenchyme-epithelial cycling associated with transient re-expression of genes normally expressed during kidney development as well as activation of growth factors and cytokine-induced signaling. In normal kidney, the Hnf-1β transcription factor drives nephrogenesis, tubulogenesis and epithelial homeostasis through the regulation of epithelial planar cell polarity and expression of developmental or tubular segment-specific genes. In a mouse model of ischemic AKI induced by a 2-hours hemorrhagic shock, we show that expression of this factor is tightly regulated in the early phase of renal repair with a biphasic expression profile (early down-regulation followed by transient over-expression). These changes are associated to tubular epithelial differentiation as assessed by KSP-cadherin and megalin-cubilin endocytic complex expression analysis. In addition, early decrease in Hnf1b expression is associated with the transient over-expression of one of its main target genes, the suppressor of cytokine signaling Socs3, which has been shown essential for renal repair. In vitro, hypoxia induced early up-regulation of Hnf-1β from 1 to 24 hours, independently of the hypoxia-inducible factor Hif-1α. When prolonged, hypoxia induced Hnf-1β down-regulation while normoxia led to Hnf-1β normalization. Last, Hnf-1β down-regulation using RNA interference in HK-2 cells led to phenotype switch from an epithelial to a mesenchyme state. Taken together, we showed that Hnf-1β may drive recovery from ischemic AKI by regulating both the expression of genes important for homeostasis control during organ repair and the state of epithelial cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Animals
  • Biomarkers / metabolism
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / genetics
  • Cell Line
  • Disease Models, Animal
  • Endocytosis / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology*
  • Female
  • Gene Expression Regulation / drug effects
  • Hepatocyte Nuclear Factor 1-beta / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 1-beta / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology*
  • Kidney / physiopathology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Prolyl-Hydroxylase Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Shock, Hemorrhagic / complications
  • Shock, Hemorrhagic / pathology
  • Shock, Hemorrhagic / physiopathology
  • Wound Healing / drug effects


  • Biomarkers
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Prolyl-Hydroxylase Inhibitors
  • RNA, Messenger
  • Hepatocyte Nuclear Factor 1-beta

Grants and funding

SF received a grant from the Fondation pour la Recherche Médicale, CC received a grant from the Société de Néphrologie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.