The proto-oncogene c-Fos transcriptionally regulates VEGF production during peritoneal inflammation

Vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-beta 1) are key mediators of adverse peritoneal membrane remodeling in peritoneal dialysis eventually leading to ultrafiltration failure. Both are pleiotropic growth factors with cell type-dependent regulation of expression and biological effects. Here we studied regulation of TGF-beta 1-induced VEGF expression in human peritoneal mesothelial cells in the absence or presence of proinflammatory stimuli, tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). Quiescent human peritoneal mesothelial cells secreted only trace amounts of VEGF. Stimulation with TGF-beta 1 resulted in time-and dose-dependent increases in VEGF mRNA expression and protein release. TNF-alpha and IL-1 beta alone had minimal effects but acted in synergy with TGF-beta 1. Combined stimulation led to induction of transcription factor c-Fos and activation of the VEGF promoter region with high-affinity binding sites for c-Fos. Inhibition of c-Fos by small interfering RNA interference or by pharmacological blockade with SR-11302 decreased VEGF promoter activity and downregulated its expression and release. Exposure of human peritoneal mesothelial cells to dialysate effluent containing increased levels of TGF-beta 1, TNF-alpha, and IL-1 beta obtained during peritonitis resulted in a dose-dependent VEGF induction that was significantly attenuated by SR-11302. Thus, dialysate TGF-beta 1, IL-1 beta, and TNF-alpha act through c-Fos to synergistically upregulate VEGF production in peritoneal mesothelium and may represent an important regulatory link between inflammation and angiogenesis in the peritoneal membrane.