BACKGROUND: Distinct histone modifications regulate gene expression in certain diseases but little is known about histone epigenetics in diabetic nephropathy. The current study examined the role of histone epigenetics in development and progression of nephropathy in db/db mice. METHODS: We studied kidney damage in 6-month-old non-diabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Histone H3K9 and H3K23 acetylation, H3K4 and H3K9 dimethylation and H3 phosphorylation at serine 10 was explored by western blotting of renal histone extracts. RESULTS: Uninephrectomy in C57BL/6 mice or onset of diabetes in type 2 diabetes reduced renal H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10. In contrast, H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 were significantly increased in uninephrectomized db/db mice. The disease pattern of these mice is characterized by an increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction. Treating uninephrectomized db/db mice with a Mcp-1/Ccl2 antagonist prevented the histopathological damage and the aforementioned histone modification abnormalities of advanced diabetic glomerulosclerosis. CONCLUSION: We conclude that advanced diabetic nephropathy is associated with increased renal H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 that enhance chromatin unfolding and gene expression.