Anti-inflammatory effect of combination therapy with rosiglitazone and all- trans retinoic acid on high glucose-induced MCP-1 response in rat mesangial cells

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) agonists and retinoid acid have antiinflammatory and anti-proliferative effects; however, their synergistic effects are not well known. We investigated the combined anti-inflammatory effect of rosiglitazone, which is a PPAR-γ agonist, and retinoid acid in rat mesangial cells (RMCs) stimulated by a high glucose (HG) concentration (30 mmol of D-glucose). The doses of rosiglitazone and all-trans retinoic acid (ATRA) which inhibited MCP-1 mRNA expression by 20-40% were selected for the study. At 48 h following incubation of RMCs in HG, MCP-1 mRNA expression was significantly increased. Rosiglitazone and ATRA lowered MCP-1 mRNA expression in a dose-dependent manner. Among the effective doses, 1.0 and 5.0 μmol/L of rosiglitazone, and 0.1 and 1.0 μmol/L of ATRA were selected for further studies. HG-induced MCP-1 mRNA expression was inhibited by combined treatment with rosiglitazone and ATRA. A combination of 1.0 μmol/L rosiglitazone and 0.1 μmol/L ATRA tended to decrease MCP-1 mRNA expression compared to the individual treatments. A combination of 5.0 μmol/L rosiglitazone and 1.0 μmol/L ATRA significantly inhibited MCP-1 mRNA expression. MCP-1 protein levels were significantly increased after 48 h of incubating the RMCs in HG. The 5.0 μmol/L dose of rosiglitazone significantly lowered MCP-1 protein synthesis while 1 μmol/L ATRA decreased MCP-1 expression stimulated by HG. Combined treatment with rosiglitazone and ATRA caused a larger decrease in MCP-1 protein synthesis compared to either treatment alone. In conclusion, the data obtained show the possibility of a synergistic effect on MCP-1 mRNA expression by rosiglitazone and ATRA.