title: p38 mitogen-activated protein kinase protects glomerular epithelial cells from complement-mediated cell injury.
abstract: In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC). We previously showed that sublytic concentration of C5b-9 triggers a variety of biological events in GEC. In the current study, we demonstrate that complement activates p38 MAPK in GEC and address the role of p38 in complement-mediated cell injury. When cultured rat GEC were stimulated with complement, p38 kinase activity and phosphorylation were increased by approximately 2.4-fold, compared with control. Treatment with p38 inhibitors significantly augmented complement-mediated cytotoxicity. In contrast, when the constitutively active mutant of transforming growth factor-beta-activated kinase 1 (TAK1), a kinase upstream of p38, was expressed in GEC in an inducible manner, cytotoxicity was significantly reduced, compared with uninduced cells. p38 inhibitors abolished the protective effect of TAK1 expression. By analogy to cultured cells, p38 activity was also increased in glomeruli from rats with PHN and treatment with the p38 inhibitor FR-167653 increased proteinuria. Complement induced phosphorylation of MAPK-associated protein kinase-2 (MAPKAPK-2), a kinase downstream of p38 in GEC. Heat shock protein (HSP27) is a cytoskeleton-interacting substrate of MAPKAPK-2. Overexpression of the wild-type HSP27, but not a non-phosphorylatable mutant, markedly reduced complement-mediated GEC injury. In summary, complement activates p38 MAPK in GEC in vitro and in glomeruli from rats with PHN. The activation of p38 MAPK appears to be cytoprotective for GEC against complement-mediated GEC injury. Phosphorylation of HSP27 may mediate this cytoprotection.
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Lamine
authors.initials: L
authors.lastname: Aoudjit
authors.forename: Monica
authors.initials: M
authors.lastname: Stanciu
authors.forename: Hongping
authors.initials: H
authors.lastname: Li
authors.forename: Serge
authors.initials: S
authors.lastname: Lemay
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D019610:Cytoprotection / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005921:Glomerulonephritis / Q000652:urine; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007678:Kidney Glomerulus / Q000166:cytology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000652:urine; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015938:Complement Membrane Attack Complex; D004791:Enzyme Inhibitors; C104334:FR 167653; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases