title: The cytoprotective role of Ras in complement-mediated glomerular epithelial cell injury.
abstract: In experimental membranous nephropathy, complement C5b-9-induced glomerular epithelial cell (GEC) injury leads to loss of glomerular permselectivity and proteinuria. Incubation of cultured GEC with antibody and serially-increasing concentrations of complement induced cytotoxicity in a dose-dependent manner. Stable expression of constitutively-active Ras (V(12)Ras) in GEC attenuated injury significantly. In the V(12)Ras-expressing GEC, disruption of the F-actin cytoskeleton with latrunculin B or swinholide A, or stabilization of F-actin with jasplakinolide reversed the cytoprotective effect of V(12)Ras. GEC displayed cortical F-actin; V(12)Ras-expressing GEC showed smaller and more rounded morphology, and decreased activity of the Rho GTPase, Rac1, compared with control GEC. Thus, the protective effect of V(12)Ras is dependent on remodeling of the actin cytoskeleton, and may be associated with a reduction in Rac activity, thereby altering the equilibrium in the activities of Rho GTPases. Activation of Ras signaling is a novel pathway to consider in developing strategies for cytoprotection in complement-mediated injury.
authors.affiliation: Department of Physiology, McGill University, Quebec, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Huynh
authors.forename: Guohui
authors.initials: G
authors.lastname: Ren
authors.forename: Joan
authors.initials: J
authors.lastname: Papillon
authors.forename: Julie
authors.initials: J
authors.lastname: Guillemette
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000633:toxicity*; D015433:Glomerulonephritis, Membranous / Q000503:physiopathology*; D015151:Immunoblotting; D007155:Immunologic Factors / Q000633:toxicity*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000293:injuries; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015938:Complement Membrane Attack Complex; D007155:Immunologic Factors; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D018631:ras Proteins