Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Lymphopenia and neutropenia are associated with subsequent incident proteinuria in Danish patients with systemic lupus erythematosus

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Collagen turnover profiles in chronic kidney disease

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations
Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7-9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease.
Original languageEnglish
JournalP L o S One
Volume7
Issue number3
Pages (from-to)e34080
ISSN1932-6203
DOIs
Publication statusPublished - 2012

    Research areas

  • Animals, Cells, Cultured, Chromatin, Cytokines, Deoxyribonuclease I, Disease Models, Animal, Female, Gene Silencing, Humans, Inflammation, Kidney, Lectins, C-Type, Lupus Nephritis, Membrane Proteins, Mice, Principal Component Analysis, RNA, Messenger, Receptors, Immunologic, Signal Transduction, Toll-Like Receptors

Most downloaded publications

No data available

ID: 36584026