Regulatory mechanisms of miRNA-21 in the progression of ischemia/reperfusion induced acute kidney injury to chronic kidney disease

Abstract Background: Acute kidney injury (AKI) induced by renal ischemia/ reperfusion (I/R) leads to a sharp decrease in renal function. Although it has been shown that miRNA-21 is dysregulated in patients who has AKI, it’s related regulation mechanism isn’t clear yet. This study aims to explore the potential mechanisms of miRNA-21-3p and miRNA-21-5p in I/R induced AKI to chronic kidney disease (CKD). Methods: The miRNA expression profile data (GSE125305) and the mRNA expression profile data (GSE148420) of rat model which include I/R induced AKI were downloaded from the NCBI⁃GEO database, and both datasets randomly divided the rats into two groups: the sham operation group and the ischemia reperfusion injury (IRI) group which received IR operation. Comprehensive analysis was used by bioinformatics method. Firstly, the miRNAs expression changes in each group at different time periods were studied. Then, the significantly different miRNAs in each group were unified, and the target genes of miRNAs were obtained. Through the protein-protein interaction (PPI) network, the mutual interaction relationships of target genes were obtained. The regulatory relationships between mRNA-mRNA and miRNA-mRNA were visualized. Next, to find the potential target genes of miRNA-21-3p and miRNA-21-5p, the significantly different mRNAs were analyzed between the group of control-3 days after surgery and the group of 3 days-7 days after surgery. Subsequently, we obtained transcription factors (TFs) that regulate pri-mir-21 and target genes, and further constructed the regulatory network of TFs-miRNA-mRNA. Finally, GO and KEGG enrichment analysis of target genes were carried out. Results: A total of 29 miRNAs with significant differences were obtained in this study. Based on the regulatory relationship between target genes and miRNAs and the changes in the expression of target genes, we believe that miRNA-21-3p tends to target to Fshb, and miRNA-21-5p tends to target to Tagln, Pdpn and Tpm1. Subsequently, we obtained the same TFs which regulate pri-mir-21 and target genes, and constructed the mutual regulatory relationship among miRNA-21-3p, miRNA-21-5p, transcription factors which include Hnf4a and Rela, as well as target genes which include Fshb, Tagln, Pdpn and Tpm1. Finally, the results of enrichment analysis of target genes include muscle organ development, positive regulation of cell adhesion, lymphangiogenesis, epithelial cell fate commitment, regulation of cell morphogenesis, peptide hormone processing, actin filament, actin binding, chemokine binding, chaperone binding, and dilated cardiomyopathy, and illustrated underlying molecular mechanisms. Conclusions: Through participating in functions and pathway of enrichment, target genes play an important role in the progression of IRI induced AKI to CKD. Meanwhile, These target genes possess a potential to be novel biomarkers and molecular targets for the diagnosis and treatment of renal diseases in the future.