NDT Advance Access originally published online on June 24, 2008
Nephrology Dialysis Transplantation 2008 23(11):3494-3500; doi:10.1093/ndt/gfn353
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Effects of epithelial-to-mesenchymal transition on acute stress response in human peritoneal mesothelial cells
Kinderdialyse, Department of Pediatrics, AKH Vienna, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
Correspondence and offprint requests to: Christoph Aufricht, Kinderdialyse, Department of Pediatrics, AKH Wien, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43-1-40400-3232; Fax: +43-1-40400-3238; E-mail: christoph.aufricht{at}meduniwien.ac.at
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Abstract |
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Background. During peritoneal dialysis, mesothelial cells undergo epithelial-to-mesenchymal transition (EMT), resulting in markedly altered protein expression. This potentially includes heat-shock proteins (HSP), the main effectors of cellular repair. Thus, chronic cellular processes, such as EMT, may influence acute stress responses and thus survival of mesothelial cells following non-lethal injury upon exposure to peritoneal dialysis fluid (PDF).
Methods. In this study, we investigated the effects of EMT on acute stress responses and cytoresistance in human peritoneal mesothelial cells. In vivo EMT was defined as a fibroblast-like growth pattern in mesothelial cells grown from peritoneal effluents, and in vitro EMT was induced by TGF-β1 in mesothelial cells grown from omental tissue. Morphologic EMT was validated by western blot analysis of EMT marker proteins (ezrin, alpha-SMA). Expression of HSP and cellular survival was evaluated in a simple in vitro PDF exposure model.
Results. In vivo and in vitro EMT resulted in marked effects on phenotypes of mesothelial cells, associated with differential HSP expression. In vivo ‘chronic’ EMT resulted in lower expression of HSP-27 and HSP-72, whereas in vitro ‘acute’ EMT was associated with increased HSP-27 and decreased HSP-72 expression. Following PDF exposure, there were no effects of in vivo EMT on the stress induction of HSP, and survival of epithelial versus fibroblast-like phenotypes was comparable. The non-stressful induction of HSP-27 following TGF-β1 pretreatment resulted in the attenuated stress induction of HSP, and in improved survival in following PDF exposure.
Conclusions. Taken together, this study confirms that mesothelial cells are not ‘unchanged’ or ‘static targets’ during the clinical course of PD treatment. The cellular processes during EMT play a complex role in acute cellular stress response and cytoresistance of mesothelial cells. Sequential analysis at different stages of EMT will be essential to provide more insights on cytoprotective cellular processes in in vitro and in vivo models of PD.
Keywords: epithelial-to-mesenchymal transition; heat-shock proteins; mesothelial cells; peritoneal dialysis; stress response
* Thorsten O. Bender is recipient of a long-term ERA-EDTA fellowship.
Received for publication: 20. 4.07
Accepted in revised form: 30. 5.08