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Co-expression Analysis Reveals Dysregulated miRNAs and miRNA-mRNA Interactions in the Development of Contrast-induced Acute Kidney Injury [miRNA]

ABSTRACT: Purpose: The pathogenesis of contrast-induced acute kidney injury (CI-AKI) has not yet been clearly understood. miRNAs are important mediators which normally work by post-transcriptional degradation of target mRNAs. Emerging evidence indicated a number of differentially expressed miRNAs in CI-AKI following intravenous contrast medium injection. However, there exist differences in the pathological mechanisms and incidences of CI-AKI between intravenous and intra-arterial contrast administration. We aimed to investigate the critical roles of dysregulated miRNAs and the correlated mRNAs in the kidney injury following intra-arterial contrast exposure. Methods: Based on a reliable CI-AKI rat model, we sought to investigate the roles of miRNA-mRNA interactions in the kidney injury following intra-arterial contrast exposure using the Illumina Genome Analyzer IIx. Results: In the study, 36 differentially expressed mature miRNAs were identified ( fold change > 1.5 and p value < 0.05) in the kidney of CI-AKI rats (n = 3) compared with controls (n = 3), consisting of 23 up-regulated and 13 down-regulated ones. Bioinformatics analysis revealed that Wnt, TGF-β, and AMPK signaling pathways were most likely to be modulated by these dysregulated miRNAs. Around 453 dysregulated genes ( fold change > 2.0 and p value < 0.05) were identified. Integrated analysis revealed 2037 putative miRNA-mRNA pairs with negative correlations. Of which, 6 differential miRNAs and 13 genes were selected for further quantitative real-time polymerase chain reaction validation (n = 6 for each group), and a well correspondence between the 2 techniques was observed. Conclusions: In conclusion, our present study contributes to the first evidence of miRNA-mRNA regulations in the development of kidney injury following an intra-arterial contrast injection route. These novel findings provide insights into the underlying mechanisms of CI-AKI.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE130796 | GEO | 2020/04/10

REPOSITORIES: GEO

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Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

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Co-expression Analysis Reveals Dysregulated miRNAs and miRNA-mRNA Interactions in the Development of Contrast-induced Acute Kidney Injury [miRNA]

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