High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition

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Title: High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition
Authors: Lynch, Julie
Nolan, Stephen
Slattery, Craig
Feighery, Ronan
Ryan, Michael P.
McMorrow, Tara
Permanent link: http://hdl.handle.net/10197/3631
Date: 24-Nov-2010
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 (aPBMC). The model was characterised 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-SMA expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products (RAGE) and through induction of TGF-β1 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.
Funding Details: Science Foundation Ireland
Higher Education Authority
Health Research Board
Other funder
Type of material: Journal Article
Publisher: Karger
Copyright (published version): 2010 Karger
Keywords: Renal fibrosis;Epithelial-mesenchymal transition;PBMC;HMGB-1
Subject LCSH: Kidneys--Fibrosis
Chromosomal proteins
Blood cells
Transforming growth factors-beta
DOI: 10.1159/000320485
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection

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