BACKGROUND: Diabetic kidney disease (DKD) is one of the main causes of renal end-stage disease. The incidence of DKD has increased substantially over the past few years. However, our understanding to the molecular mechanism of DKD is still essential, and an effective treatment has not been developed. AIM: We aimed to explore the molecule mechanism in the development of DKD, and provide a comparison of DKD in different compartments. MATERIALS AND METHODS: In this study, we implemented a system biology approach and analyzed gene expression profiles in 22 microdissected human renal glomerular and 22 tubule samples from healthy patients and patients with DKD. RESULTS: The WGCNA (Weighted Gene Co-expression Network Analysis) analysis identified 10 modules of genes with high topological overlap in tubuli and 12 modules in glomeruli. Several TFs (transcription factors) were found expressed in both compartments, such as ETS1, ETV4, JUN, LITAF, NFE2, RARG and STAT5A. These genes may be used as therapeutic targets for DKD. By comparing the modules in the two compartments, we found that dysregulation of cell proliferation may significantly contribute to the development of DKD. Furthermore, our results concluded that DKD may be an immune-mediated degenerative disease. CONCLUSIONS: Our studies identified multiple genes that may play an important role in the pathogenesis of DKD and provided a system understanding of the potential relationships among these genes. We hope our study could aid in understanding of DKD and could provide the basis for DKD biomarker discovery.