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

• Published in: Journal of molecular cell biology Vol. 8; no. 6; pp. 477 - 491
• Main Authors: He, Fengxia, Zhou, Mengya, Yu, Tianyi, Zhao, Dan, Zhang, Jing, Qiu, Wen, Lu, Yanlai, Liu, Yu, Wang, Lulu, Wang, Yingwei
• Format: Journal Article
• Language: English
• Published: United States 01.12.2016
• Subjects: Acetylation; Activating Transcription Factor 3 - genetics; Activating Transcription Factor 3 - metabolism; Animals; Apoptosis; Cell Cycle Proteins - metabolism; Cell Line; Complement Membrane Attack Complex - metabolism; E1A-Associated p300 Protein - metabolism; Early Growth Response Protein 1 - metabolism; Gene Silencing; Lysine - metabolism; Male; Mesangial Cells - metabolism; Mesangial Cells - pathology; Nephritis - complications; Nephritis - metabolism; Nuclear Proteins - metabolism; Proteinuria - complications; Proteinuria - metabolism; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thy-1 Antigens; Transcription, Genetic; Up-Regulation; acetylation; transcription factor; apoptosis; glomerular mesangial cells; Thy-1 nephritis; sublytic C5b-9
• ISSN: 1674-2788; 1759-4685
• DOI: 10.1093/jmcb/mjw021

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.