title: Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.
abstract: Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Lovisa
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Tampe
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Vadnagara
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Julienne L
authors.identifier: http://orcid.org/0000-0001-9914-0430
authors.initials: JL
authors.lastname: Carstens
authors.affiliation: Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
authors.affiliation: Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Tsvetelina
authors.initials: T
authors.lastname: Pentcheva-Hoang
authors.affiliation: Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hersharan
authors.initials: H
authors.lastname: Nischal
authors.affiliation: Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D016195:G2 Phase; D006801:Humans; D007668:Kidney / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D027362:Organic Anion Transport Protein 1 / Q000235:genetics
chemical_list: D027362:Organic Anion Transport Protein 1; D051398:Aquaporin 1