title: High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition.
abstract: BACKGROUND
  high-mobility group box protein 1 (HMGB-1) is a chromatin-binding protein that bends DNA, thereby facilitating gene transcription. HMGB-1 has also been observed as an extracellular secreted protein in serum of patients with sepsis and has putative intracellular signalling effects regulating the production of interleukin-1 and tumour necrosis factor in a number of inflammatory conditions.
  
  
  METHODS
  we established a model of immune-mediated epithelial-mesenchymal transition (EMT) in human proximal tubular epithelial cells (PTECs). PTECs were cultured with conditioned medium containing supernatant from activated peripheral blood mononuclear cells (aPBMCs). The model was characterized using phenotypic and transcriptomic approaches and suppression subtractive hybridisation was performed to identify differentially regulated genes.
  
  
  RESULTS
  activation of PBMCs resulted in increased secretion of HMGB-1. In addition, treatment of PTECs with aPBMC-conditioned medium resulted in significant upregulation of HMGB-1 in PTECs. Direct treatment of PTECs with recombinant human HMGB-1 induced alterations in epithelial morphology consistent with EMT including reduced E-cadherin expression, increased α-smooth muscle actin expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products and through induction of transforming growth factor-β(1) secretion from PTECs.
  
  
  CONCLUSIONS
  these results suggest that HMGB-1 is a key mediator of immune-mediated EMT of PTECs and a potentially important signalling molecule in the development of renal fibrosis.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Julie
authors.initials: J
authors.lastname: Lynch
authors.forename: Stephen
authors.initials: S
authors.lastname: Nolan
authors.forename: Craig
authors.initials: C
authors.lastname: Slattery
authors.forename: Ronan
authors.initials: R
authors.lastname: Feighery
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ryan
authors.forename: Tara
authors.initials: T
authors.lastname: McMorrow
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000276:immunology*; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015820:Cadherins; D024243:HMGB1 Protein; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta