Identification of hub genes and transcription factor-miRNA-mRNA pathways in mice and human renal ischemia-reperfusion injury

Abstract

Background Renal ischemia-reperfusion injury (IRI) is a disease with high incidence rate in kidney related surgery. Micro RNA (miRNA) and transcription factors (TFs) are widely involved in the process of renal IRI through regulation of their target genes. However, the regulatory relationships and functional roles of TFs, miRNAs and mRNAs in the progression of renal IRI are insufficiently understood. The present study aimed to clarify the underlying mechanism of regulatory relationships in renal IRI. Methods Six gene expression profiles were downloaded from Gene Expression Omnibus (GEO). Differently expressed genes (DEGs) and differently expressed miRNAs (DEMs) were identified through RRA integrated analysis of mRNA datasets (GSE39548, GSE87025, GSE52004, GSE71647, and GSE131288) and miRNA datasets (GSE29495). miRDB and TransmiR v2.0 database were applied to predict target genes of miRNA and TFs, respectively. DEGs were applied for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, followed with construction of protein-protein interaction (PPI) network. Then, the TF-miRNA-mRNA network was constructed. Correlation coefficient and ROC analysis were used to verify regulatory relationship between genes and their diagnostic value in GSE52004. Furthermore, in independent mouse RNA-seq datasets GSE98622, human RNA-seq GSE134386 and in vitro, the expression of hub genes and genes from the network were observed and correlation coefficient and ROC analysis were validated. Results A total of 21 DEMs and 187 DEGs were identified in renal IRI group compared to control group. The results of PPI analysis showed 15 hub genes. The TF-miRNA-mRNA regulatory network was constructed and several important pathways were identified and further verified, including Junb-miR-223-Ranbp3l, Cebpb-miR-223-Ranbp3l, Cebpb-miR-21-Ranbp3l and Cebpb-miR-181b-Bsnd. Four regulatory loops were identified, including Fosl2-miR-155, Fosl2-miR-146a, Cebpb-miR-155 and Mafk-miR-25. The hub genes and genes in the network showed good diagnostic value in mice and human. Conclusions In this study, we found 15 hub genes and several TF-miRNA-mRNA pathways, which are helpful for understanding the molecular and regulatory mechanisms in renal IRI. Junb-miR-223-Ranbp3l, Cebpb-miR-223-Ranbp3l, Cebpb-miR-21-Ranbp3l and Cebpb-miR-181b-Bsnd were the most important pathways, while Spp1, Fos, Timp1, Tnc, Fosl2 and Junb were the most important hub genes. Fosl2-miR-155, Fosl2-miR-146a, Cebpb-miR-155 and Mafk-miR-25 might be the negative feedback loops in renal IRI.

Identification of hub genes associated with acute kidney injury induced by renal ischemia–reperfusion injury in mice

“…In addition to its high expression in animal AKI models, Fos expression has also been demonstrated to be upregulated in severely damaged human kidney tissues compared to that in normal kidney tissues. It was further found that Fos in the IR group was also upregulated in HK-2 cells in vitro ( Ke et al, 2021 ). The conclusions of these studies all support our current research that Fos is more likely to be involved in biological regulation and interconnected with IRI-AKI and could act as a biomarker, which might be used to assess the severity of IRI and verify the effectiveness of treatments.…”

Multi-omic Analysis of Primary Human Kidney Tissues Identifies Medulla-Specific Gene Expression Patterns

“…For example, the transcription factor gene SIM1 has a similar pattern of expression as POU3F3 in the renal collecting system of the developing mouse kidney 23 and pronephros of zebrafish 24 . Another potential POU3F3 target gene, RANBP3L has been shown to play a role in BMP signaling pathways 25 , ischemia reperfusion injury 26 and has been linked to regulation of blood pressure via urinary potassium excretion 27 . CADM1 , which has a distal nephron/medullary pattern of expression overlapping with POU3F3 28 , appears to be shed in nephropathies 29 and may serve as a urinary biomarker of medullary injury 30 .…”

Identification of biomarkers associated with oxidative stress-related genes in postmenopausal osteoporosis

“…Meanwhile, miRNA expression is also mediated by TF, thus forming a complex upstream and downstream regulatory network of miRNA, namely TF-miRNA-mRNA (40,41). TF-miR-NA-mRNA could help correlate the interaction of transcription factors, miRNA and target genes together, and visualize a network map, thus exploring potential key molecules more intuitively and conveniently (42,43). In this study, the TF-miRNA-mRNA network construction results identified that RB1, RBCA1 and JDP2 regulated DDIT3, besides, RELA, ABL1 and NFKB1 regulated FOXO3.…”