Integrated Analysis of the CircRNA-Based ceRNA Network in Renal Fibrosis Induced by Ischemia Reperfusion Injury

Abstract

Background: Circular RNAs (circRNAs), which have broad posttranscriptional regulatory potencies, are involved in the pathogenesis of fibrotic diseases and are promising diagnostic biomarkers and therapeutic targets. However, their specific roles in renal fibrosis remain elusive.Methods: A robust unilateral renal ischemia reperfusion injury (UIRI) mouse model was established to recapitulate the pathophysiology of renal fibrosis. The expression of circRNAs, miRNAs, and mRNAs was profiled by high-throughput RNA sequencing technology.Results: In total, 4983 circRNAs, 216 miRNAs, and 6371 mRNAs were differentially expressed in UIRI-induced fibrotic kidneys. Candidate circRNAs and miRNAs were validated by RT–qPCR in both UIRI and unilateral ureteral obstruction mouse models. Bioinformatic analysis indicated that the parental genes of the differentially expressed circRNAs were predominantly implicated in focal adhesion, adhesion junctions, and regulation of actin cytoskeleton pathways. Through circRNA-miRNA-mRNA construction, we identified two hub genes, circSlc8a1 and circApoe, that targeted a large number of differentially expressed miRNAs and mRNAs related to metabolism and cytokine–cytokine receptor pathways, respectively.Conclusion: CircRNAs were dysregulated in the UIRI model and might be potentially involved in the pathogenesis of renal fibrosis. Research efforts should focus on unravelling the functions of aberrantly expressed circRNAs in renal fibrosis to uncover biomarkers that would enable early diagnosis and the design of prompt therapeutic interventions to prevent disease progression.

Circ_0047339 promotes the activation of fibroblasts and affects the development of urethral stricture by targeting the miR-4691-5p/TSP-1 axis

“…The differential circRNA was significantly related to ECM–receptor interaction, Arrhythmogenic right ventricular cardiomyopathy (ARVC), Thyroid hormone synthesis, and Proteoglycans in cancer and Focal adhesion. CircRNA could combine with miRNA in a targeted way and indirectly regulate the translation of mRNA 27 . The miRanda software was used to select the differentially expressed circRNA to predict the target miRNA, and the circRNA–miRNA network diagram was drawn.…”

“…At present, there are few research articles on the relationship between circRNA and urethral stricture. The existing literature mainly focuses on renal fibrosis 20 , 27 . Other studies have found that circRNA is related to the mechanism of keloid formation 29 – 31 .…”

Circular RNAs Variously Participate in Coronary Atherogenesis

“…High-throughput RNA sequencing (RNA-Seq) has made it possible to identify thousands of circRNAs involved in physiological processes and in the pathogenesis of various diseases [ 78 , 79 , 80 , 81 , 82 ]. The most commonly used way to detect differentially expressed circRNAs (DECs) includes a comparative analysis of their representation in experimental and control biological samples using microarrays or RNA-Seq.…”

Circular RNAs in Acute Kidney Injury: Roles in Pathophysiology and Implications for Clinical Management

“…In another study of unilateral IRI murine kidney model 4983 circRNAs were found to be differentially expressed, and bioinformatic analysis showed that the parental genes of these circRNAs were involved in focal adhesion, adhesion junctions, and the regulation of actin cytoskeleton pathways. Two hub genes, namely, circ-SLC8A1 (mmu_circ_0000823) and circ-APOE (mmu_circ_0014064), were associated with a large number of differentially expressed miRNAs and mRNAs on bioinformatic analysis [ 51 ]. These circRNAs are also aberrantly expressed in other conditions such as solid organ tumours and CKD, where they are associated with cell proliferation, angiogenesis, cell migration, and epithelial-to-mesenchymal transition including in the induction and propagation of renal fibrosis.…”