RAGE expression in the human peritoneal membrane.
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 NFkappaBp65, VEGF, transforming growth factor (TGF)-beta1, 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 NFkappaB-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-beta1, SMA and NFkappaBp65 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 NFkappaB 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 NFkappaB-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.
Kihm
Lars P
LP
Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany.
Wibisono
Dennis
D
Müller-Krebs
Sandra
S
Pfisterer
Friederike
F
Morath
Christian
C
Gross
Marie L
ML
Morcos
Michael
M
Seregin
Yuri
Y
Bierhaus
Angelika
A
Nawroth
Peter P
PP
Zeier
Martin
M
Schwenger
Vedat
V
D016022:Case-Control Studies; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010530:Peritoneal Dialysis / Q000009:adverse effects; D010537:Peritoneum / Q000098:blood supply / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic