Identification of Hub Genes and Potential ceRNA Networks of Diabetic Nephropathy by Weighted Gene Co-Expression Network Analysis.

Guoqing Li,Qiong Wei,Gaifang Liu,Yingqi Lv,Jun Zhang,Hui Wang,Ling Li,Dechen Liu,Zheng Ye

doi:10.3389/fgene.2021.767654

Abstract

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, and is the main cause of end-stage renal disease. The exact molecular mechanism of DN is not fully understood. The aim of this study was to identify novel biomarkers and mechanisms for DN disease progression by weighted gene co-expression network analysis (WGCNA). From the GSE142153 dataset based on the peripheral blood monouclear cells (PBMC) of DN, we identified 234 genes through WGCNA and differential expression analysis. Gene Ontology (GO) annotations mainly included inflammatory response, leukocyte cell-cell adhesion, and positive regulation of proteolysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mostly included IL-17 signaling pathway, MAPK signaling pathway, and PPAR signaling pathway in DN. A total of four hub genes (IL6, CXCL8, MMP9 and ATF3) were identified by cytoscape, and the relative expression levels of hub genes were also confirmed by RT-qPCR. ROC curve analysis determined that the expression of the four genes could distinguish DN from controls (the area under the curve is all greater than 0.8), and Pearson correlation coefficient analysis suggested that the expression of the four genes was related to estimated glomerular filtration rate (eGFR) of DN. Finally, through database prediction and literature screening, we constructed lncRNA-miRNA-mRNA network. We propose that NEAT1/XIST/KCNQ1T1-let-7b-5p-IL6, NEAT1/XIST-miR-93-5p-CXCL8 and NEAT1/XIST/KCNQ1T1-miR-27a-3p/miR-16-5p-ATF3 might be potential RNA regulatory pathways to regulate the disease progression of early DN. In conclusion, we identified four hub genes, namely, IL6, CXCL8, MMP9, and ATF3, as markers for early diagnosis of DN, and provided insight into the mechanisms of disease development in DN at the transcriptome level.

Highlights

Diabetic nephropathy (DN) is the main microvascular complication of diabetes mellitus, occurring in approximately 30–40% of patients with type 1 or type 2 diabetes, and often leads to end-stage renal disease (Alicic et al, 2017; Wang et al, 2019)
Module-trait relationship analyses showed that multiple modules were related to DN, and it clearly indicated that the green module was Identification of the Co-DEGs of Green Module
We proposed that NEAT1/XIST/KCNQ1T1-let-7b-5p-IL6 (Figure 9D), NEAT1/XIST-miR-93-5p-CXCL8 (Figure 9E) and NEAT1/XIST/KCNQ1T1- miR-27a-3p/miR-16-5p-ATF3 (Figure 9F) might be potential RNA regulatory pathways to regulate the disease progression of early DN

Summary

Introduction

Diabetic nephropathy (DN) is the main microvascular complication of diabetes mellitus, occurring in approximately 30–40% of patients with type 1 or type 2 diabetes, and often leads to end-stage renal disease (Alicic et al, 2017; Wang et al, 2019). The pathogenesis factors of DN reported in earlier studies include advanced glycosylation products, protein kinase activity, abnormal lipid metabolism and hemodynamic changes. With the development of molecular biology, many pathways have been found to be involved in the development of DN, such as TNF signaling pathway, MAPK signaling pathway, and AGE-RAGE signaling pathway (Omote et al, 2014; Wang et al, 2019).

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