Diabetic nephropathy (DN) is a diabetic complication that seriously endangers human health. Its pathogenesis involves a variety of factors. The purpose of this paper is to determine key genes in the disease progression that will be potential therapeutic targets of DN. Based on gene expression profiles and the databases of interactions of proteins-proteins, transcription factors-genes, transcription factors-miRNAs and miRNAs-genes, the differentially expressed genes of DN were screened. The regulatory network of DN differential genes was established and key genes of DN were identified using the entity grammar system. According to the regulatory interaction between genes, key genes were defined as the ones that could regulate the state of other genes from abnormal towards normal expression. Identified key genes include BMP2 (bone morphogenetic protein 2), VEGFA (vascular endothelial growth factor A), F3 (coagulation factor III/tissue factor), EGR2 (early growth response protein 2), CDS1 (CDP- diacylglycerol synthase 1) and PLCE1 (phospholipase C epsilon 1). These findings provide clues for the successful drug development of DN.