title: The proto-oncogene c-Fos transcriptionally regulates VEGF production during peritoneal inflammation.
abstract: Vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) 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-β1-induced VEGF expression in human peritoneal mesothelial cells in the absence or presence of proinflammatory stimuli, tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). Quiescent human peritoneal mesothelial cells secreted only trace amounts of VEGF. Stimulation with TGF-β1 resulted in time- and dose-dependent increases in VEGF mRNA expression and protein release. TNF-α and IL-1β alone had minimal effects but acted in synergy with TGF-β1. 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-β1, TNF-α, and IL-1β obtained during peritonitis resulted in a dose-dependent VEGF induction that was significantly attenuated by SR-11302. Thus, dialysate TGF-β1, IL-1β, and TNF-α 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.
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.forename: Janusz
authors.initials: J
authors.lastname: Witowski
authors.forename: Philine
authors.initials: P
authors.lastname: Wagner
authors.forename: Isa
authors.initials: I
authors.lastname: Annett Schramm
authors.forename: Edyta
authors.initials: E
authors.lastname: Kawka
authors.forename: Aurelie
authors.initials: A
authors.lastname: Philippe
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.forename: Achim
authors.initials: A
authors.lastname: Jörres
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D015314:Dialysis Solutions / Q000378:metabolism / Q000627:therapeutic use; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D010537:Peritoneum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D015314:Dialysis Solutions; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A