title: Response of VEGF to activation of viral receptors and TNFα in human mesangial cells.
abstract: Vascular endothelial growth factor (VEGF) plays an important role in glomerular homeostasis as well as in the pathogenesis of kidney diseases as glomerulonephritis (GN) and diabetic nephropathy. Mesangial cells (MC), which are an integral part of the functional glomerular filtration barrier in that providing structural support, can behave like inflammatory cells and produce mediators as chemokines and growth factors; they are known to express viral receptors, with TLR3 having been attributed relevance in viral disease-associated GN. Experiments were performed on human MC in cell culture. Stimulation experiments were performed with poly (I:C) and hepatitis C RNA from patients with hepatitis C infection. We hereby show a TLR3-mediated upregulation of VEGF and its receptor subtype 2 (VEGF-R2) in human MC upon activation of viral receptors by poly (I:C) and hepatitis C virus. The increase in VEGF expression levels is further enhanced by tumor necrosis factor alpha (TNFα) which also induces the cytokines IL-6 and IL-8 as well as the chemokines MCP-1 and RANTES. These effects are potentiated by preincubation of MC with poly (I:C), just as the induction of the viral receptors TLR3, RIG-1, and MDA5 themselves. Moreover, MCP-1 itself is able to significantly increase mesangial VEGF expression. Therefore, with VEGF and VEGF-R2 being induced upon viral receptor activation in human MC, a novel role of TLR3 in mediating glomerular damage in virally induced or aggravated GN is inferred. TNFα and MCP-1 are seemingly important in amplifying VEGF effects in the setting of virally induced inflammation, with TNFα being also able to induce other mediators of glomerular pathology in GN.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Merkle
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Franziska
authors.initials: F
authors.lastname: Belling
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
mesh_terms: D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D000072640:Interferon-Induced Helicase, IFIH1; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D011070:Poly I-C / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D018836:Inflammation Mediators; C437968:PLAAT4 protein, human; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D011991:Receptors, Virus; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C