Mesothelial RAGE activation by AGEs enhances VEGF release and potentiates capillary tube formation

Advanced glycation end-products (AGEs) inhibit ischemia-induced angiogenesis but are potential triggers of neoangiogenesis that occurs in peritoneal dialysis (PD) patients. We investigated whether the effect of glucose and AGEs on human peritoneal mesothelial cells (HPMCs) might alter the release of vascular endothelial growth factor (VEGF) and subsequently the formation of capillary tubes by human umbilical vein endothelial cells (HUVECs). HPMCs were exposed to glucose and the glycated protein Nvarepsilon-(carboxymethyl)lysine-human serum albumin (CML-HSA) and VEGF production was measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Capillary tube formation by HUVECs in presence of HPMC supernatant or co-cultured with HPMC was investigated. AGE and VEGF levels in PD effluents from 11 patients were measured. CML-HSA stimulated VEGF production by HPMCs, P<0.001. Glucose and AGE inhibited capillary tube formation by HUVECs, P<0.001. HPMC supernatant potentiated capillary tube formation, P<0.001. In co-culture with HPMC capillary tube formation was increased, especially by HPMCs stimulated by CML-HSA, P<0.001. Anti-VEGF antibody limited this effect, P<0.001. Preincubation of HPMCs with anti-receptor for AGEs (RAGE) antibody reduced capillary tube formation, P<0.001. AGE and VEGF levels in PD effluents were increased during long dwell time, P<0.05 and P<0.001, respectively. In a co-culture system, we showed that VEGF production by HPMC favors capillary tube formation through mesothelial RAGE activation and could explain neoangiogenesis in PD patient.