SUMOylation of PPARγ by rosiglitazone prevents LPS-induced NCoR degradation mediating down regulation of chemokines expression in renal proximal tubular cells

• Published in: PloS one Vol. 8; no. 11; p. e79815
• Main Authors: Lu, Ying, Zhou, Qiao, Shi, Yongbing, Liu, Jian, Zhong, Fang, Hao, Xu, Li, Cong, Chen, Nan, Wang, Weiming
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.11.2013; Public Library of Science (PLoS)
• Subjects: Activation; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Binding sites; Cell Line; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemokines; Chemokines - genetics; Chemokines - metabolism; Chromatin; Co-Repressor Proteins - genetics; Co-Repressor Proteins - metabolism; Cytokines; Cytotoxicity; Degradation; Diabetes; Down-Regulation - drug effects; Down-Regulation - genetics; Gene expression; Humans; Immunoprecipitation; Infiltration; Inflammation; Inhibition; Injury prevention; Interleukin; Interleukin 8; Kidney diseases; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidneys; Kinases; Leukocytes (neutrophilic); Ligases - genetics; Ligases - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Nephrology; NF-κB protein; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic - genetics; Proteins; Proteolysis - drug effects; Rodents; Rosiglitazone; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; SUMO protein; Sumoylation - drug effects; Sumoylation - genetics; Thiazolidinediones - pharmacology; Toxicity; Ubiquitin; Ubiquitin-protein ligase; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0079815

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.