Chronic hyperglycaemia promotes the production of pro-inflammatory and pro-fibrotic mediators that lead to the development of chronic kidney disease. Increasing evidence implicates histone methylation in this process. Set7, a lysine methyltransferase that mono-methylates histone and non-histone proteins, has been associated with increased expression of pro-fibrotic genes in various models of kidney disease. This project aims to further define the role of Set7 in the development of diabetic nephropathy and evaluate it as a target for developing reno-protective therapies in diabetes. For this purpose, diabetes-induced structural and functional kidney damage was studied in ApoE–/– and Set7–/–ApoE–/– male mice. Mice were euthanised after 10 weeks of streptozotocin-induced diabetes and kidneys were harvested for molecular and histological analyses. Set7 deletion conferred renal protection as evidenced by attenuated albuminuria, mesangial expansion scores and glomerular deposition of collagen I and IV. The expression of pro-fibrotic and pro-inflammatory genes such as Fn1 and Icam1 was also attenuated in the kidneys of diabetic Set7–/–ApoE–/– mice in association with reduced H3K4me1 levels at their promoters. Global renal cortical gene expression by RNA-seq followed by pathway analysis revealed that Set7 is associated with pathways related to mitochondrial function in diabetic mice. Furthermore, analysis of the H3K4me1 profile shows a global reduction in the levels of this histone mark near gene transcriptional start sites and enhancers in diabetic Set7–/–ApoE–/– compared to diabetic ApoE–/– mice. Collectively, our results suggest that targeting Set7 may represent a strategy for developing therapies aimed at reducing the burden of diabetic nephropathy.