Chronic hyperglycaemia promotes the production of pro-inflammatory and pro-fibrotic mediators that lead to the development of chronic kidney disease. Increasing evidence implicates the Set7 lysine mono-methyltransferase in this pathological process in various models of chronic kidney disease. This study aims to define the role of Set7 in the development of diabetic nephropathy and evaluate it as a target for therapeutic intervention. For this purpose, diabetes-induced renal damage, as defined by histological and molecular changes, was studied in ApoE-/- and Set7-/-ApoE-/- male mice compared to non-diabetic controls 10 weeks after the induction of diabetes. Set7 deletion conferred renal protection as evidenced by attenuated albuminuria, mesangial expansion and glomerular deposition of collagen I and IV in diabetic Set7-/-ApoE-/- compared to diabetic ApoE-/- mice. RNA profiling by sequencing revealed that diabetes causes widespread gene expression changes in the kidney that are attenuated by Set7 knock-out. We confirmed gene expression changes associated with Set7 using qRT-PCR. Furthermore, treatment of cultured human podocytes and mesangial cells with (R)-PFI-2, a selective Set7 inhibitor, attenuated high glucose and TGFb1-mediated increases in pro-inflammatory and pro-fibrotic gene expression. Additionally, Gene Set Enrichment Analysis (GSEA) of the RNA-seq data revealed that many diabetes-induced, Set7-dependent genes are associated with the transcription factor Tcf21, a key mediator of kidney development and podocyte function. We performed protein interaction studies and confirmed that Set7 interacts with Tcf21. We hypothesise that Tcf21 represents a novel Set7 methylation target and our results implicate this transcription factor in the pathology of diabetic nephropathy. Collectively, our results suggest that Set7 may represent a target for developing therapies aimed at reducing the burden of diabetic nephropathy.