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NDT Advance Access published online on May 13, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn272
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


RAGE expression in the human peritoneal membrane

Lars P. Kihm1, Dennis Wibisono1, Sandra Müller-Krebs1, Friederike Pfisterer1, Christian Morath1, Marie L. Gross2, Michael Morcos1, Yuri Seregin1, Angelika Bierhaus1, Peter P. Nawroth1, Martin Zeier1 and Vedat Schwenger1

1 Department of Nephrology and Endocrinology 2 Department of Pathology, University of Heidelberg, Germany

Correspondence and offprint requests to: Vedat Schwenger, Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Tel: +49-6221-91120; Fax: +49-6221-9112-229; E-mail: vedat.schwenger{at}med.uni-heidelberg.de



  Abstract

Background. Experimental animal models have demonstrated that the interaction of advanced glycation end-products (AGE) with their receptor RAGE is, at least in part, responsible for peritoneal damage. This study investigates the in vivo expression of RAGE in the peritoneal membrane of uraemic human patients.

Methods. Peritoneal biopsies of 89 subjects (48 uraemic and 41 healthy age-matched patients) were examined. The expression of CD3, IL-6, activated NF{kappa}Bp65, VEGF, transforming growth factor (TGF)-β1, smooth-muscle actin (SMA), methylglyoxal (MGO) and RAGE was analysed immunohistochemically. Additionally, in 4 of the 48 uraemic patients, peritoneal biopsies were repeated after 15 months at the time of catheter removal to analyse the above parameters and the extent of NF{kappa}B-binding activity determined by electrophoretic mobility shift assay (EMSA) in the long-term follow-up.

Results. In comparison to the healthy controls, uraemic patients showed a significant increase in fibrosis, angiogenesis, submesothelial thickness, MGO-derived protein adducts, RAGE, IL-6, VEGF, TGF-β1, SMA and NF{kappa}Bp65 in their peritonea. Four patients, followed up longitudinally from peritoneal dialysis (PD) catheter insertion to removal, demonstrated further significant increase in the above parameters, particularly in RAGE expression and NF{kappa}B activation.

Conclusions. Along with a higher expression of several indicators for inflammation, angiogenesis, fibrosis and AGE accumulation, the peritoneal membrane of the uraemic patients showed an increased submesothelial thickness and a marked induction of RAGE expression and NF{kappa}B-binding activity, which both further increased after PD treatment. These findings in human peritoneum support the concept of the AGE–RAGE interaction being crucial in peritoneal damage due to uraemia and PD.

Keywords: AGE; peritoneum; peritoneal damage; RAGE

Received for publication: 21. 6.07
Accepted in revised form: 18. 4.08


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