title: Basic fibroblast growth factor selectively enhances TNF-alpha-induced apoptotic cell death in glomerular endothelial cells: effects on apoptotic signaling pathways.
abstract: Endothelial cell damage of glomeruli and kidney arterioles seems to play a pivotal role in several pathologic situations, such as Gram-negative sepsis, glomerulonephritis, and acute renal failure. Bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) have been identified as potent inducers of apoptotic cell death in bovine glomerular endothelial cells. Both agents elicited apoptotic DNA laddering within 12 to 24 h. Basic fibroblast growth factor (bFGF) was generally described as a protective factor for endothelial cells against radiation-, TNF-alpha-, and UV-light-induced programmed cell death. Therefore, whether bFGF also affects apoptosis of microvascular endothelial cells was questioned. Surprising was that simultaneous treatment of glomerular endothelial cells with bFGF and either LPS or TNF-alpha left LPS-induced death unaffected, whereas TNF-alpha-induced death induction was potentiated, amounting to 48.9+/-6.3% versus 22.4+/-4.3% DNA degradation with TNF-alpha alone. Comparably, acidic FGF also selectively potentiated TNF-alpha-induced apoptosis. In mechanistic terms, bFGF synergistically increased TNF-alpha-induced mitochondrial permeability transition, the release of cytochrome c from mitochondria to the cytosol, and upregulation of the proapoptotic protein Bak and significantly enhanced activation of caspase-8 protease activity. In contrast, stress-activated protein kinase and nuclear factor kappaB activation, which represent primary signals of TNF/TNF receptor interaction, downregulation of the antiapoptotic protein Bcl-x(L), and caspase-3-like protease activation, were unaffected. As bFGF did not affect LPS-induced apoptotic cell death, bFGF also left LPS-induced Bak upregulation and Bcl-x(L) downregulation unaffected. The results point to a selective bFGF-mediated enhancement of distinct proapoptotic pathways induced by TNF-alpha in glomerular endothelial cells.
authors.affiliation: Pharmacenter Frankfurt, Klinikum der Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Udo K
authors.initials: UK
authors.lastname: Messmer
authors.affiliation: Department of Medicine, Kantonsspital Luzern, Luzern, Switzerland.
authors.forename: Verena A
authors.initials: VA
authors.lastname: Briner
authors.affiliation: Pharmacenter Frankfurt, Klinikum der Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D015703:Antigens, CD; D004338:Drug Combinations; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases