Inhibitory effects of rosiglitazone on lipopolysaccharide-induced inflammation in a murine model and HK-2 cells.

BACKGROUND: Inflammation may play an important role in the pathogenesis of kidney disease. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators. The purpose of this study was to examine the effects of rosiglitazone on lipopolysaccharide (LPS)-induced kidney inflammation and to explore the mechanism of its renoprotection.

METHODS: Mice were treated with LPS with or without pretreatment with rosiglitazone. Blood urea nitrogen (BUN), creatinine levels, the urinary albumin-to-creatinine ratio, macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, PPAR-γ expression, and NF-κB and PPAR-γ activity were investigated. HK-2 cells were maintained under defined in vitro conditions, treated with either rosiglitazone and/or the PPAR-γ antagonist GW9662, and then stimulated with LPS. MCP-1, IL-8, IL-6, NF-κB activity and PPAR-γ expression were investigated.

RESULTS: Compared to the LPS only group, pretreatment with rosiglitazone in vivo significantly attenuated the BUN levels macrophage infiltration, MCP-1 overexpression and NF-κB activity (p < 0.05). Rosiglitazone also restored PPAR-γ expression and protein activity, which were reduced significantly in the LPS only group (p < 0.05). Furthermore, in the LPS-stimulated HK-2 cells, rosiglitazone downregulated MCP-1, IL-8 and IL-6 expression as well as NF-κB activation and increased PPAR-γ expression (p < 0.05). These effects were diminished by GW9662.

CONCLUSION: These results showed that pretreatment with rosiglitazone could attenuate kidney inflammation through the activation of PPAR-γ, suppression of MCP-1 overproduction and NF-κB activation. Rosiglitazone had a protective effect via a PPAR-γ-dependent pathway in LPS-treated HK-2 cells.