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

Lei Wei,Limin Liu,Zhixiang Yu,Shiren Sun,Ying Zhou,Liya Wang,Xiao Bai,Ming Bai

doi:10.3389/fgene.2021.793182

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.

Highlights

Chronic kidney disease (CKD) affects 8–16% of the world population and contributes significantly to global mortality and morbidity (Nelson et al, 2019)
The epithelial marker E-cadherin was decreased, and the mesenchymal marker vimentin was increased in the unilateral renal ischemia reperfusion injury (UIRI) group compared to the sham group (Figure 1C)
The mRNA levels of fibrotic markers, including transforming growth factor beta 1 (Tgfb1), tissue inhibitor of metalloproteinase (Timp1), fibronectin (Fn), and collagen1a (Col1a), were elevated significantly after UIRI (Figure 1D). These results indicated that at 2 weeks after UIRI, renal histopathologic examination exhibited signs of extensive tubulointerstitial fibrosis, suggesting that the transition to CKD was already occurring

Summary

Introduction

Chronic kidney disease (CKD) affects 8–16% of the world population and contributes significantly to global mortality and morbidity (Nelson et al, 2019). Further in-depth exploration of the molecular mechanism of IRI-induced renal fibrosis is needed to facilitate the discovery of potential biomarkers and new therapeutic targets for CKD. Noncoding RNAs (ncRNAs), vital components of epigenetics that make up of more than 90% of the transcriptome, are delicately regulated and play pivotal roles in a range of kidney disorders (Fan et al, 2020; Lin et al, 2020; Chen et al, 2021; Ren and Wang, 2021). 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. Their specific roles in renal fibrosis remain elusive

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Results

Discussion

Conclusion