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

J Mol Cell Biol. 2016 Dec;8(6):477-491. doi: 10.1093/jmcb/mjw021. Epub 2016 May 4.

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.

Keywords: Thy-1 nephritis; acetylation; apoptosis; glomerular mesangial cells; sublytic C5b-9; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Thy-1 Antigens
  • Transcription, Genetic
  • Up-Regulation

Substances

  • 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