title: Sublytic C5b-9 triggers glomerular mesangial cell apoptosis in rat Thy-1 nephritis via Gadd45 activation mediated by Egr-1 and p300-dependent ATF3 acetylation.
abstract: The apoptosis of glomerular mesangial cells (GMCs) is considered to be an important contributor to the initiation and development of rat Thy-1 nephritis (Thy-1N) and is accompanied by sublytic C5b-9 deposition. However, the mechanism by which sublytic C5b-9 triggers GMC apoptosis has not been elucidated. In this study, functional and histological examinations were performed on GMCs treated with sublytic C5b-9 (in vitro) and renal tissues of Thy-1N rats (in vivo). The in vitro studies found that sublytic C5b-9 could trigger GMC apoptosis through upregulating Egr-1, ATF3, and Gadd45 expression. Egr-1-mediated post-transcriptional modulation of ATF3, Egr-1/ATF3-enhanced Gadd45 promoter activity, and p300-mediated ATF3 acetylation were all involved in GMC apoptosis. More importantly, the effective binding elements for Egr-1 and ATF3 to Gadd45β/γ promoters and the ATF3 acetylation site were identified. In vivo, silencing renal p300, Egr-1, ATF3, and Gadd45β/γ significantly decreased GMC apoptosis, secondary GMC proliferation, and urinary protein secretion in Thy-1N rats. Together, these findings implicate that sublytic C5b-9-induced activation of Egr-1/p300-ATF3/Gadd45 axis plays a critical role in GMC apoptosis in Thy-1N rats.
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Mengya
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China wangyw1508@njmu.edu.cn.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D020868:Gene Silencing; D008239:Lysine / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology*; D009393:Nephritis / Q000150:complications / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011507:Proteinuria / Q000150:complications / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018800:Thy-1 Antigens; D014158:Transcription, Genetic; D015854:Up-Regulation; D000097642:GADD45 Proteins
chemical_list: D051700:Activating Transcription Factor 3; D018797:Cell Cycle Proteins; D015938:Complement Membrane Attack Complex; D050881:E1A-Associated p300 Protein; D051766:Early Growth Response Protein 1; D008239:Lysine; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018800:Thy-1 Antigens; C497108:Atf3 protein, rat; C486110:Egr1 protein, rat; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C494362:Ep300 protein, rat
keywords: Thy-1 nephritis; acetylation; apoptosis; glomerular mesangial cells; sublytic C5b-9; transcription factor