The formation of methylglyoxal (MG), a reactive dicarbonyl compound, is accelerated under hyperglycemia, presumably contributing to tissue injury in diabetes. On the other hand, prostaglandin E2 (PGE2) has been implicated in glomerular hyperfiltration, a characteristic change in the early stage of diabetic nephropathy. We therefore examined whether MG was capable of inducing PGE2 production in rat mesangial cells (RMC) to address a possible mechanism by which hyperglycemia-derived dicarbonyls accelerated the development of diabetic nephropathy. RMC were incubated with 0 - 200 microM of MG, followed by determination of secreted PGE2 by enzyme immunoassay (EIA). We further investigated the intracellular mechanisms mediating the MG-induced PGE2 synthesis, focusing particularly on cyclooxygenase-2 (COX-2) and the MAPK superfamily. Our results indicated that MG induced PGE2 production in a dose-dependent manner, accompanied by augmentation of COX-2 mRNA expression. This MG-induced PGE2 production was significantly suppressed by inhibiting either ERK1/2 or p38 MAPK, implicating involvement of the MAPK superfamily. Our results suggest a potential role of MG in the development of diabetic nephropathy through PGE2 production, and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.