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NDT Advance Access published online on June 6, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl271
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 21, 2006
Accepted April 18, 2006

Original Article

Myofibroblast transdifferentiation of mesothelial cells is mediated by rage and contributes to peritoneal fibrosis in uraemia

An S. De Vriese 1 *, Ronald G. Tilton 2, Siska Mortier 3, and Norbert H. Lameire 3

1 The Renal Unit, University Hospital, Ghent, Belgium; The Renal Unit, AZ Sint-Jan AV, Brugge, Belgium
2 The Division of Endocrinology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
3 The Renal Unit, University Hospital, Ghent, Belgium

* To whom correspondence should be addressed.
An S. De Vriese, E-mail: an.devriese{at}azbrugge.be



  Abstract

Background. Uraemia is associated with fibrosis of the peritoneal membrane, even prior to the start of peritoneal dialysis. Increased carbonyl stress and the resultant formation of advanced glycation end-products (AGEs) are potentially involved. The interaction of AGEs with their cell surface receptor for AGE (RAGE) induces sustained cellular activation, including the production of the fibrogenic growth factor-{beta} (TGF-{beta}). TGF-{beta} is pivotal in the process of epithelial-to-mesenchymal transition with the acquisition of myofibroblast characteristics. We investigated whether antagonism of RAGE prevents uraemia-induced peritoneal fibrosis. In addition, we examined whether myofibroblast transdifferentiation of mesothelial cells contributes to peritoneal fibrosis in uraemia.

Methods. Uraemia was induced in rats by subtotal nephrectomy. Uraemic and age-matched sham-operated rats were treated for 6 weeks with neutralizing monoclonal anti-RAGE antibodies or placebo. Expression of AGE, RAGE, cytokeratin and {alpha}-smooth muscle actin was evaluated using immunohistochemistry. TGF-{beta} expression was examined with immunostaining and western blotting, and Snail expression with western blotting. Fibrosis was quantified with a picro-sirius red staining and measurement of the hydroxyproline content of the tissue.

Results. Uraemia resulted in the accumulation of AGE, up-regulation of RAGE and TGF-{beta} and the development of interstitial fibrosis and vascular sclerosis in the peritoneal membrane. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by colocalization of cytokeratin and {alpha}-smooth muscle actin in submesothelial and interstitial fibrotic tissue. The antagonism of RAGE prevented the up-regulation of TGF-{beta}, epithelial-to-mesenchymal transition of mesothelial cells and fibrosis in uraemia.

Conclusion. The ligand engagement of RAGE and the subsequent up-regulation of TGF-{beta} induces peritoneal fibrosis in chronic uraemia. The process may be mediated by the conversion of mesothelial cells into myofibroblasts.

Keywords: AGE; myofibroblast; peritoneal membrane; RAGE; uraemia; TGF-{beta}.
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