title: Stat3 Controls Tubulointerstitial Communication during CKD.
abstract: In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.|Service d'Explorations Fonctionnelles, and.
authors.forename: Frank
authors.initials: F
authors.lastname: Bienaimé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Mordi
authors.initials: M
authors.lastname: Muorah
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Lucie
authors.initials: L
authors.lastname: Yammine
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Martine
authors.initials: M
authors.lastname: Burtin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Clément
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Willian
authors.initials: W
authors.lastname: Baron
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Garbay
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Amandine
authors.initials: A
authors.lastname: Viau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Broueilh
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blanc
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Dorien
authors.initials: D
authors.lastname: Peters
authors.affiliation: Department of Biotechnology and Health Sciences, Molecular Biotechnology Center, Torino University, Turin, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.|Service de Néphrologie-Transplantation, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.|Service d'Explorations Fonctionnelles, and.
authors.forename: Gérard
authors.initials: G
authors.lastname: Friedlander
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling.
authors.forename: Morgan
authors.initials: M
authors.lastname: Gallazzini
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling, fabiola.terzi@inserm.fr.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
mesh_terms: D000818:Animals; D002450:Cell Communication; D005260:Female; D007684:Kidney Tubules / Q000166:cytology*; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor
keywords: Cell Signaling; Pathophysiology of Renal Disease and Progression; chronic kidney disease; renal fibrosis; renal tubular epithelial cells; transcriptional profiling