Advanced glycation end products (AGEs) and their interaction with the receptor for advanced glycation end products (RAGE) play an important role in diabetic vascular complications. The current study demonstrated that AGEs significantly increased RAGE expression and the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) in human umbilical vein endothelial cell-derived line ECV304 cells. RAGE antisense RNA partially inhibited the expression of TNF-alpha and IL-6 induced by AGEs. Oligonucleotide microarray was used to identify the genes that respond to RAGE activation. Phospholipase C beta 1 (PLC beta 1), phospholipase C beta 4 (PLC beta 4) and calcium/calmodulin-dependent protein kinase IV (CAMK IV) which associated with Ca(2+) signaling were upregulated. The rise of intracellular calcium and the NF-kappaB promoter activity induced by AGEs were suppressed by RAGE antisense RNA, PLC inhibitor U73122 and dominant negative CAMK IV, respectively. These findings suggest that PLC/CAMK IV-NF-kappaB is involved in RAGE mediated signaling pathway in human endothelial cells.