Histone modifications, especially histone acetylation and methylation, are important for gene expression regulation in diabetic nephropathy. However, the general epigenetic changes in mesangial cells have not been characterized. We examined Histone Deacetylases (HDACs) and Histone Methyltransferases (HMTs), representative histone-modifying enzymes, during transient and persistent stimulation with High Glucose (HG) in Rat Mesangial Cells (RMCs). RMCs were incubated with 5.5 or 30 mmol/L Dglucose and were divided into 4 groups according to glucose stimulation over 24 h periods: group 1, no HG; group 2, initial HG followed by Low Glucose (LG); group 3, alternative HG and LG; group 4, persistent HG. The mRNA levels of interleukin (IL)-6 and IL1β were significantly higher in group 4 than group 1, indicating that transient and persistent exposure to HG could induce an inflammatory response. Both classes I (HDAC2, 3, 8) and II (HDAC4, 5) HDACs decreased as exposure to HG increased, and this decrease was particularly strong for HDAC2. However, class III HDAC levels did not differ among groups. Sirt1, 2, and 3 differed only slightly among groups. Mixed Lineage Leukaemia (MLL) 1, MLL2, and MLL3 were not affected by HG exposure, but other HMTs, e.g. G9a, Setdb1, and Suv39h1, showed a decrease. In conclusion, transient or persistent HG stimulation induced changes in inflammatory and histone-modifying deacetylase and methyltransferase in RMCs. These results suggested that HG decreased classes I and II HDACs and repressive HMTs, which could upregulates gene expression in RMCs.