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SUMOylation of PPARγ by rosiglitazone prevents LPS-induced NCoR degradation mediating down regulation of chemokines expression in renal proximal tubular cells.
- Source :
-
PloS one [PLoS One] 2013 Nov 08; Vol. 8 (11), pp. e79815. Date of Electronic Publication: 2013 Nov 08 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Rosiglitazone (RGL), a synthetic agonist for peroxisome proliferator activated receptor γ (PPARγ), exhibits a potent anti-inflammatory activity by attenuating local infiltration of neutrophils and monocytes in the renal interstitium. To evaluate the mechanisms that account for inhibiting inflammatory cells infiltration, we investigated the effect of RGL on chemokines secretion and nuclear factor-kappa B (NF-κB) activation in human renal proximal tubular cells (PTCs). We demonstrated that RGL significantly inhibited lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production in a dose-dependent manner, without appreciable cytotoxicity. Chromatin immunoprecipitation (ChIP) assays clearly revealed that, RGL inhibited p65 binding to IL-8/MCP-1 gene promoters in LPS-stimulated PTCs. Interestingly, further experiments showed RGL reversed LPS-induced nuclear receptor corepressor (NCoR) degradation. In addition, knockdown of protein inhibitor of activated STAT1 (PIAS1), an indispensable small ubiquitin-like modifier (SUMO) ligase, abrogated the effects of RGL on antagonizing LPS-induced IL-8/MCP-1 overexpression and NCoR degradation. These findings suggest that, RGL activates PPARγ SUMOylation, inhibiting NCoR degradation and NF-κB activation in LPS-stimulated PTCs, which in turn decrease chemokines expression. The results unveil a new mechanism triggered by RGL for prevention of tubular inflammatory injury.
- Subjects :
- Anti-Inflammatory Agents pharmacology
Cell Line
Chemokine CCL2 genetics
Chemokine CCL2 metabolism
Chemokines genetics
Co-Repressor Proteins genetics
Down-Regulation genetics
Humans
Kidney Tubules, Proximal drug effects
Ligases genetics
Ligases metabolism
Lipopolysaccharides pharmacology
PPAR gamma genetics
Promoter Regions, Genetic genetics
Proteolysis drug effects
Rosiglitazone
STAT1 Transcription Factor genetics
STAT1 Transcription Factor metabolism
Sumoylation genetics
Chemokines metabolism
Co-Repressor Proteins metabolism
Down-Regulation drug effects
Kidney Tubules, Proximal metabolism
PPAR gamma metabolism
Sumoylation drug effects
Thiazolidinediones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24260304
- Full Text :
- https://doi.org/10.1371/journal.pone.0079815