Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products

Abstract

SUMMARYAutoclaving peritoneal dialysate fluid (PDF) degrades glucose into glucose degradation products (GDPs) that impair peritoneal mesothelial cell functions. While glycation processes leading to formation of advanced glycation end-products (AGE) were viewed commonly as being mediated by glucose present in the PDF, recent evidence indicates that certain GDPs are even more powerful inducers of AGE formation than glucose per se . In the present study, we examined the expression and modulation of AGE receptors on human peritoneal mesothelial cells (HPMC) cultured with GDPs, conventional PDF or PDF with low GDP content. HPMC cultured with GDPs differentially modulated AGE receptors (including RAGE, AGE-R1, AGE-R2 and AGE-R3) expression in a dose-dependent manner. At subtoxic concentrations, GDPs increased RAGE mRNA expression in HPMC. 2-furaldehyde (FurA), methylglyoxal (M-Glx) and 3,4-dideoxy-glucosone-3-Ene (3,4-DGE) increased the expression of AGE-R1 and RAGE, the receptors that are associated with toxic effects. These three GDPs up-regulated the AGE synthesis by cultured HPMC. In parallel, these GDPs also increased the expression of vascular endothelial growth factor (VEGF) in HPMC. PDF with lower GDP content exerted less cytotoxic effect than traditional heat-sterilized PDF. Both PDF preparations up-regulated the protein expression of RAGE and VEGF. However, the up-regulation of VEGF in HPMC following 24-h culture with conventional PDF was higher than values from HPMC cultured with PDF containing low GDP. We have demonstrated, for the first time, that in addition to RAGE, other AGE receptors including AGE-R1, AGE-R2 and AGE-R3 are expressed on HPMC. Different GDPs exert differential regulation on the expression of these receptors on HPMC. The interactions between GDPs and AGE receptors may bear biological relevance to the intraperitoneal homeostasis and membrane integrity.

Angiogenic Activity of the Peritoneal Mesothelium: Implications for Peritoneal Dialysis

“…These observations were in line with earlier data showing that the intensity of peritoneal AGE accumulation in PD patients correlated with changes in peritoneal transport and ultrafiltration (Honda et al, 1999;Nakayama et al, 1997). Moreover, mesothelial cells were found to bear a receptor for AGEs (RAGE) and to upregulate its expression following exposure to GDP in either in vitro (Lai et al, 2004) or in vivo setting (Mortier et al, 2004). In turn, incubation of mesothelial cells with AGEs led to a dose-dependent increase in VEGF production (Boulanger et al, 2007;Mandl-Weber et al, 2002).…”

“…In turn, incubation of mesothelial cells with AGEs led to a dose-dependent increase in VEGF production (Boulanger et al, 2007;Mandl-Weber et al, 2002). Interestingly, GDP-induced VEGF release by mesothelial cells could be reduced by aminoguanidine, an inhibitor of AGE formation (Lai et al, 2004). Also, a rise in peritoneal VEGF expression and vascular density that was induced in wild-type mice by chronic exposure to GDP-containing fluids, did not occur in RAGE-deficient animals (Schwenger et al, 2006).…”

“…Subsequent experiments confirmed that extensive peritonea l e x p r e s s i o n o f V E G F i n r a t s r e c e i v i n g methylglyoxal-containing PD fluids was associated with neoangiogenesis and increased permeability (Hirahara et al, 2006). Furthermore, it has been demonstrated that direct in vitro exposure of mesothelial cells to several GDPs (methylglyoxal, 3,4-dideoxy-glucosone-3-ene, 2-furaldehyde) resulted in an increased VEGF expression (Inagi et al, 1999;Lai et al, 2004;Leung et al, 2005). The adverse effects of GDPs on the peritoneal membrane can also be mediated through advanced glycation-end products (AGEs).…”

Membrane Biology During Peritoneal Dialysis

“…Recently, other AGE receptors, including AGE-R-1 (p 60), AGE-R-2 (p 90) and AGE-R-3 (gallectin-3) are also found to be expressed on MCs [17]. Different GDPs exert differential regulation on the regulation and expression of these receptors on human peritoneal MCs [17]. However, the functional significance of these various forms has not yet been completely delineated.…”

“…The key pathophysiological step seems to be GDP-dependent AGE formation in the uremic milieu, through which an enhanced expression of RAGE in the peritoneum could be observed. Recently, other AGE receptors, including AGE-R-1 (p 60), AGE-R-2 (p 90) and AGE-R-3 (gallectin-3) are also found to be expressed on MCs [17]. Different GDPs exert differential regulation on the regulation and expression of these receptors on human peritoneal MCs [17].…”