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Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products

Vedat Schwenger^*, Christian Morath^*, Alexander Salava^*, Kerstin Amann, Yuri Seregin^*, Reinhold Deppisch, Eberhard Ritz^*, Angelika Bierhaus^*, Peter P. Nawroth^* and Martin Zeier^*

^* Department of Medicine, Divisions of Nephrology and Endocrinology, University of Heidelberg, Heidelberg, Germany; Department of Pathology, University of Erlangen-Nurnberg, Erlangen, Germany; and Gambro Corporate Research, Hechingen, Germany

Address correspondence to: Dr. Vedat Schwenger, Department of Medicine/Division of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Phone: +49-6221-9112-601; Fax: +49-6221-9112-229; E-mail: vedat.schwenger{at}med.uni-heidelberg.de

Received for publication February 10, 2005. Accepted for publication October 18, 2005.

Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE–receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3⁺ T cells, increased NF-B binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3⁺ T cells and NF-B binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE–RAGE interaction.

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