title: Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis through the Cascade Pathway of MEKK2-p38 MAPK-IRF-1-TRADD-Caspase 8 in Rat Thy-1 Nephritis.
abstract: The apoptosis of glomerular mesangial cells (GMCs) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is primarily triggered by sublytic C5b-9. However, the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In this study, we demonstrate that expressions of TNFR1-associated death domain-containing protein (TRADD) and IFN regulatory factor-1 (IRF-1) were simultaneously upregulated in the renal tissue of Thy-1N rats (in vivo) and in GMCs under sublytic C5b-9 stimulation (in vitro). In vitro, TRADD was confirmed to be a downstream gene of IRF-1, because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Increased phosphorylation of p38 MAPK was verified to contribute to IRF-1 and TRADD production and caspase 8 activation, as well as to GMC apoptosis induced by sublytic C5b-9. Furthermore, phosphorylation of MEK kinase 2 (MEKK2) mediated p38 MAPK activation. More importantly, three sites (Ser153/164/239) of MEKK2 phosphorylation were identified and demonstrated to be necessary for p38 MAPK activation. In addition, silencing of renal MEKK2, IRF-1, and TRADD genes or inhibition of p38 MAPK activation in vivo had obvious inhibitory effects on GMC apoptosis, secondary proliferation, and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 may play an important role in GMC apoptosis following exposure to sublytic C5b-9 in rat Thy-1N.
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Ganqian
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Yongting
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China; and.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Mengya
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China; wangyw1508@njmu.edu.cn.|Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000494:pharmacology*; D015432:Glomerulonephritis, Membranoproliferative / Q000209:etiology* / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000502:physiology*; D048730:MAP Kinase Kinase Kinase 2 / Q000502:physiology*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053199:TNF Receptor-Associated Death Domain Protein / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D015938:Complement Membrane Attack Complex; D050856:Interferon Regulatory Factor-1; D053199:TNF Receptor-Associated Death Domain Protein; D048051:p38 Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D053181:Caspase 8