Identification of PDK4 as Hub Gene for Diabetic Nephropathy Using Co-Expression Network Analysis

Abstract

Introduction: Diabetic nephropathy (DN) is related to type 1 and type 2 diabetes. They are the leading cause of end-stage renal disease (ESRD), but the underling specific pathogenesis of DN is not yet clear. Our study was conducted to explore how DN changed the transcriptome profiles in kidney. Methods: The gene expression profile of micro-dissected glomeruli of 41 type 2 diabetic nephropathy patients and 20 healthy controls were included. The sample data set GSE86804 was obtained from the GEO database. Differentially expressed genes (DEGs) were analyzed in R with the limma package and the important modules were found by weighted gene co-expression network analysis (WGCNA) clustering. The modules were then analyzed based on Gene Ontology (GO) gene set enrichment analysis, and the hub genes were found out. We next validated the hub gene, PDK4, in a cell model of DN. We also constructed the PDK4-related PPI network to investigate the correlation between PDK4 expression and other genes. Results: Heat map and volcano map were drawn to illustrate the mRNA expression profile of 1204 DEGs in both samples of diabetic nephropathy patients and the control group. Using WGCNA, we selected the blue module in which genes showed the strongest correlation with the phenotype and the smallest P-value. We also identified PDK4 as a hub gene. PDK4 expression was upregulated in human diabetic kidney tissue. Moreover, PDK4 was speculated to play a role in glomerular basement membrane development, kidney development according to the enrichment of functions and signaling pathways. Furthermore, PDK4, and two key genes GSTA2 and G6PC protein expression were verified highly expressed in the cell model of DN. Conclusion: During the pathogenesis of DN, many genes may change expression in a coordinated manner. The discovery of PDK4 as key gene using WGCNA is of great significance for the development of new treatment strategies to block the development of DN.

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“…GSTA2, GSTA3, and GSTO2 all belong to the glutathione S-transferase family. Among them, GSTA2 is closely associated with diabetic nephropathy ( Han et al, 2023 ; Xue et al, 2023 ), whereas GSTA3 is primarily studied in tumors ( Ahmed et al, 2022 ). GSTO2 is primarily associated with ocular diseases ( Saadat et al, 2012 ; Bamdad et al, 2021 ).…”