title: SUMOylation of PPARγ by rosiglitazone prevents LPS-induced NCoR degradation mediating down regulation of chemokines expression in renal proximal tubular cells.
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.
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China ; Department of Nephrology, Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Zhong
authors.forename: Xu
authors.initials: X
authors.lastname: Hao
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.forename: Weiming
authors.initials: W
authors.lastname: Wang
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects* / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D056970:Co-Repressor Proteins; D008070:Lipopolysaccharides; D047495:PPAR gamma; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008025:Ligases