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: Fengxia He, Mengya Zhou, Tianyi Yu, Dan Zhao, Jing Zhang, Wen Qiu, Yanlai Lu, Yu Liu, Lulu Wang, Yingwei Wang
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 8 Issue 6 Pg. 477-491 (12 2016) ISSN: 1759-4685 [Electronic] United States
• PMID: 27190312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Chemical References

• Activating Transcription Factor 3
• Atf3 protein, rat
• Cell Cycle Proteins
• Complement Membrane Attack Complex
• Early Growth Response Protein 1
• Egr1 protein, rat
• Gadd45a protein, rat
• Nuclear Proteins
• RNA, Messenger
• Thy-1 Antigens
• E1A-Associated p300 Protein
• Ep300 protein, rat
• Lysine

Topics

• Acetylation
• Activating Transcription Factor 3 (genetics, 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, pathology)
• Nephritis (complications, metabolism)
• Nuclear Proteins (metabolism)
• Proteinuria (complications, metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats, Sprague-Dawley
• Thy-1 Antigens
• Transcription, Genetic
• Up-Regulation