Diabetes nephropathy (DN) is the leading cause of end stage renal disease and it affects up to 40% of diabetic patients. In addition to hyperglycemia, genetic factors are thought to contribute to the development of DN, but few if any genetic factors have been convincingly linked to DN. Other possible mechanisms may involve epigenetic regulation of glucose-stimulated gene activity which was suggested to explain long-term effects of poor glycemic control on risk of diabetic complications, often referred to as metabolic memory. Osteopontin (OPN) is one of the genes upregulated in kidneys from diabetic mouse models as well as humans with DN, and suggested to play an important role in the pathogenesis of DN. In this study, we demonstrated that OPN gene expression is upregulated in the kidneys of a hyperglycemia diabetes mouse model SUR1-E1506K, and glucose-stimulated OPN gene expression is strongly associated with increases in activating histone marks H3K9ac, H3K4me1 and H3K4me3 and decrease in inactivating mark H3K27me3 in the promoter region of OPN gene. These findings were replicated in human mesangial cells treated with high glucose. Further proof for the involvement of histone acetylation and methylation in glucose-induced changes in OPN gene expression was obtained by manipulating histone modifications thereby OPN gene expression by histone deacetylase (HDAC) inhibitor trichostatin A and histone methyltransferase (HMT) inhibitor MM-102. We conclude that glucose is a potent inducer of histone acetylation and methylation, which in turn leads to upregulation of OPN gene expression. Treatment targeting histone marks may therefore represent an alternative method to protect kidneys from deleterious effects of glucose. (C) 2015 Elsevier Inc. All rights reserved.