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IRF9 is primarily localized in the nucleus, and by promoting PPARα transactivation, it accelerates lipid catabolism and mitigates hepatic steatosis, suggesting a key role for IRF9 in metabolic functions that is independent of its role in immunity.[ 13 ]

Our results show that IRF9, STAT2, and NFKB2 are important TFs during the progression of DN. Among them, STAT2 is a DRG, which indicates that STAT2 might be posttranslationally modified during the progression of DN.

Excessive cellular growth is a major contributor to pathological changes associated with DN. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. High glucose and ANG II activate intracellular signaling processes, including the polyol pathway and the generation of reactive oxygen species. These pathways activate the JAK /signal transducers and activators of transcription ( STAT ) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerular mesangial cells, contributing to DN.[ 11 ]

Nuclear factor-κB ( NF-κB ) is the most important TF in the pathogenesis of DN. NF-κB1 or NF-κB2 is bound to REL (V-rel avian reticuloendotheliosis viral oncogene homolog), RELA , and RELB to form the NF-κB complex, which binds to the promoter regions of several genes, including those encoding TGF-β1 , AKR1B1 (aldo-keto reductase family 1, member B1), CCL2 (CC chemokine ligand 2), and ICAM1 (intercellular adhesion molecule 1). NF-κB is also integrated in various biological pathways that are functionally involved in the pathogenesis of DN, such as PKCβ , RAS , AGE accumulation, and oxidative stress.

There were two strengths in our study. First, we enrolled patients at two stages of DN, especially including the early stage of DN, which provided us a great opportunity to investigate the special gene regulatory pattern in the initiation stage of DN. Second, we utilized the DCEA and DRA to explore the changes in transcription regulatory relationships in different stages of DN, which might lead to a greater understanding of the molecular mechanism of DN. One limitation of our studies was that the study was performed in Chinese Han patients; thus, the results might not be applied to other ethnic groups. Another limitation was that the results should be validated in cell culture and animal models.

In summary, this study utilized the gene expression profiles of glomeruli from DN patients to further investigate the potential transcriptional regulatory mechanisms in the early and late stages of the disease. We observed that the gene coexpression relationship changes occurred mainly in the early stage of DN, while the gene expression changes occurred mainly during the progression of DN. Although the results should be further validated, this study offered additional insights into the transcriptional regulatory mechanisms of DN.

Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website .

Financial support and sponsorship

The work was supported by grants from the National Key Research and Development Program of China (2016YFC0904103), the National Natural Science Foundation of China (No. 81500556, No. 81500548, and No. 81500547), and the Innovation Capability Development Project of Jiangsu Province (No. BM2015004).