Inhibitory effect of troglitazone on tumor necrosis factor alpha-induced expression of monocyte chemoattractant protein-1 in human mesangial cells

Insulin resistance is one of the risk factors for the progression of atherosclerosis and glomerulosclerosis. Recently, the new oral insulin-sensitizing agent troglitazone has been thought to offer potential in the treatment of diabetes. If adopted for this use, it might be helpful in protecting against the development of atherosclerosis and microvascular complications via its improvement of insulin resistance. However, it has not yet been clarified whether troglitazone acts directly on the vascular cells and inhibits the progression of atherosclerosis, including glomerulosclerosis. Meanwhile, monocyte chemoattractant protein-1 (MCP-1) is known to play an important role in the pathogenesis of atherosclerosis and glomerulosclerosis through the induction of monocyte migration. Therefore, we investigated the effect of troglitazone on the expression of MCP-1 in human mesangial cells (HMCs), HMCs were treated with or without troglitazone (1 or 10 mu mol/L) in the presence or absence of tumor necrosis factor alpha (TNF-alpha) at various concentrations (50 or 500 ng/mL), and then MCP-1 secretion from the HMCs was measured. We found that TNF-alpha increased the secretion of MCP-1 by 55-fold versus the control and troglitazone significantly inhibited this TNF-alpha-induced increase in MCP-1 secretion (49.3%), Moreover, Northern blot analysis showed that troglitazone decreased the MCP-1 mRNA level in HMCs. We demonstrated that alpha-tocopherol also inhibited TNF-alpha-induced MCP-1 production in HMCs, although its effects were not as strong as troglitazone. The present study indicates that troglitazone may prevent the progression of atherosclerosis by inhibiting MCP-1 expression in mesangial cells. Copyright (C) 2000 by W.B. Saunders Company.