Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease

Abstract

Background/Aims: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. Methods: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. Results: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. Conclusion: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets.

Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease

“…To expand the potential use of uBBOX1, the differential expression of BBOX1 mRNA in other types of CKD was further examined using an integrative bioinformatics approach. The basic characteristics of the included datasets have been described in our previous study [8]. As shown in Table 6, compared with normal kidney tissues, tubular BBOX1 mRNA expression was either not significantly changed or slightly upregulated in other types of CKD including hypertensive nephropathy (relative expression: 0.929, adjusted p = 0.438), focal segmental glomerulosclerosis (relative expression: 1.17, adjusted p = 0.134), IgA nephropathy (relative expression: 0.965, adjusted p = 0.662) and membranous nephropathy (relative expression: 1.28, adjusted p = 0.0045).…”

“…To minimize platform variations, the platform filtering criterion was set to “Affymetrix U133″, which included three types of microarrays (Human Genome U133 Plus 2.0 Array, Human Genome U133A 2.0 Array, and Human Genome U133A&B). The searching criteria for other types of CKD can be found in our previous study [8].…”

Genomic approaches in the search for molecular biomarkers in chronic kidney disease

“…Most of the studies were performed on small numbers, with only three studies analysing results from over 100 patients (Table 11 ). A recent integrative bioinformatics analysis of 250 gene expression datasets of healthy renal tissues and those with various types of established CKD, including DKD, hypertensive nephropathy, and glomerulonephritis, retrieved from the Gene Expression Omnibus repository ( https://www.ncbi.nlm.nih.gov/geo/ ) has identified nine genes significantly differentially expressed both in diseased glomeruli and tubules ( IFI16 , COL3A1 , ZFP36 , NR4A3 , DUSP1 , FOSB , HBB , FN1 , PTPRC ) [ 154 ]. Gene Ontology, pathway enrichment analysis and protein interaction network showed dysregulation of several metabolic, immune response, signalling pathways, platelet dysfunction, and extracellular matrix (ECM) organization in the glomeruli and signalling pathways in the tubules, mainly associated with apoptosis, PI3K-Akt, MAPK, and TGF-β [ 154 ].…”

Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

“…Unilateral ureteral obstruction (UUO) is a classic animal model that can simulate obstructive nephropathy ( Chevalier et al, 2009 ). Recently, with the rapid development of microarray and high-throughput sequencing technologies, the mechanisms of RF at the genomic level have been increasingly explored ( Lee et al, 2014 ; Zhou et al, 2018 ; Higashi et al, 2019 ). We analyzed two comprehensive and integrated miRNA datasets (GSE118340 and GSE42716) and one mRNA dataset (GSE69101) from the Gene Expression Omnibus (GEO) database.…”