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

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

Author information

1
Département de Néphrologie et Transplantation d'organes, CHU Rangueil, Toulouse, France. faguer.s@chu-toulouse.fr

Abstract

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.

PMID:
23704921
PMCID:
PMC3660442
DOI:
10.1371/journal.pone.0063585
[Indexed for MEDLINE]
Free PMC Article
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