title: Hnf-1β transcription factor is an early hif-1α-independent marker of epithelial hypoxia and controls renal repair.
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.
authors.affiliation: Département de Néphrologie et Transplantation d'organes, CHU Rangueil, Toulouse, France. faguer.s@chu-toulouse.fr
authors.forename: Stanislas
authors.initials: S
authors.lastname: Faguer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mayeur
authors.forename: Audrey
authors.initials: A
authors.lastname: Casemayou
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Pageaud
authors.forename: Claire
authors.initials: C
authors.lastname: Courtellemont
authors.forename: Claire
authors.initials: C
authors.lastname: Cartery
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournie
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051539:Hepatocyte Nuclear Factor 1-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D012333:RNA, Messenger; D051539:Hepatocyte Nuclear Factor 1-beta