Identification of Key Candidate Genes and Chemical Perturbagens in Diabetic Kidney Disease Using Integrated Bioinformatics Analysis.

Zhuo Gao,Li-Na Sui,Xin-Lun Li,Aishwarya S,Xiao-Mei Li

doi:10.3389/fendo.2021.721202

Abstract

Globally, nearly 40 percent of all diabetic patients develop serious diabetic kidney disease (DKD). The identification of the potential early-stage biomarkers and elucidation of their underlying molecular mechanisms in DKD are required. In this study, we performed integrated bioinformatics analysis on the expression profiles GSE111154, GSE30528 and GSE30529 associated with early diabetic nephropathy (EDN), glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. A total of 1,241, 318 and 280 differentially expressed genes (DEGs) were identified for GSE30258, GSE30529, and GSE111154 respectively. Subsequently, 280 upregulated and 27 downregulated DEGs shared between the three GSE datasets were identified. Further analysis of the gene expression levels conducted on the hub genes revealed SPARC (Secreted Protein Acidic And Cysteine Rich), POSTN (periostin), LUM (Lumican), KNG1 (Kininogen 1), FN1 (Fibronectin 1), VCAN (Versican) and PTPRO (Protein Tyrosine Phosphatase Receptor Type O) having potential roles in DKD progression. FN1, LUM and VCAN were identified as upregulated genes for GDKD whereas the downregulation of PTPRO was associated with all three diseases. Both POSTN and SPARC were identified as the overexpressed putative biomarkers whereas KNG1 was found as downregulated in TDKD. Additionally, we also identified two drugs, namely pidorubicine, a topoisomerase inhibitor (LINCS ID- BRD-K04548931) and Polo-like kinase inhibitor (LINCS ID- BRD-K41652870) having the validated role in reversing the differential gene expression patterns observed in the three GSE datasets used. Collectively, this study aids in the understanding of the molecular drivers, critical genes and pathways that underlie DKD initiation and progression.

Highlights

Diabetes is a major global health crisis projected to affect 642 million people by 2040 [1]
Upon setting the cut-off criterion as log2FC > 1.5 and P < 0.05, we identified 1,241, 318 and 280 differentially expressed genes (DEGs) from GSE30528, GSE30529 and GSE111154, respectively
We have identified 44 upregulated and 23 downregulated genes overlapped between the early diabetic nephropathy (EDN) and glomerular DKD (GDKD), 188 upregulated and 5 downregulated genes were found overlapped between the GDKD and tubular DKD (TDKD), and 52 upregulated genes were found commonly between the EDN and TDKD

Summary

Introduction

Diabetes is a major global health crisis projected to affect 642 million people by 2040 [1]. According to the statistics from the World Health Organization (WHO), the rapid rise in the population prevalence in low- and middle- income countries led to the dramatic rise in the number of diabetic patients from 108 million in 1980 to 422 million in 2014. Nearly 40 percent of all diabetic patients develop serious diabetic kidney disease (DKD) [2]. Diabetes is one of the leading causes of both end-stage renal disease (ESRD) and chronic kidney disease (CKD) [3, 4]. The mortality due to the DKD rose by 94 percent between 1990 and 2012 [5]

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