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Circular RNAs in kidney disease and cancer

This article has been updated

Abstract

Circular RNAs (circRNAs) are a class of endogenously expressed regulatory RNAs with a single-stranded circular structure. They are generated by back splicing and their expression can be tightly regulated by RNA binding proteins. Cytoplasmic circRNAs can function as molecular sponges that inhibit microRNA–target interactions and protein function or as templates for the efficient generation of peptides via rolling circle amplification. They can also act as molecular scaffolds that enhance the reaction kinetics of enzyme–substrate interactions. In the nucleus, circRNAs might facilitate chromatin modifications and promote gene expression. CircRNAs are resistant to degradation and can be packaged in extracellular vesicles and transported in the circulation. Initial studies suggest that circRNAs have roles in kidney disease and associated cardiovascular complications. They have been implicated in hypertensive nephropathy, diabetic kidney disease, glomerular disease, acute kidney injury and kidney allograft rejection, as well as in microvascular and macrovascular complications of chronic kidney disease, including atherosclerotic vascular disease. In addition, several circRNAs have been reported to have oncogenic or tumour suppressor roles or to regulate drug resistance in kidney cancer. The available data suggest that circRNAs could be promising diagnostic and/or prognostic biomarkers and potential therapeutic targets for kidney disease, cardiovascular disease and kidney cancer.

Key points

  • CircRNAs are regulatory RNA molecules with a closed circular structure that are generated by back splicing of precursor mRNAs.

  • Functions of cytoplasmic circRNAs include sponging of microRNAs and proteins, scaffolding of enzyme–substrate interactions and acting as templates for protein translation.

  • Nuclear-enriched circRNAs can also act as molecular sponges and promote gene expression by interacting with chromatin remodelling complexes and increasing RNA polymerase II activity.

  • CircRNAs have been implicated in the pathogenesis of kidney diseases, cardiovascular complications of chronic kidney disease and kidney cancer, and are promising potential therapeutic targets.

  • CircRNAs are promising biomarkers of disease owing to their high stability and packaging in extracellular vesicles.

  • Potential circRNA-based therapeutic approaches include modulation of native circRNAs and the application of artificial circRNAs with designer molecular functions.

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Fig. 1: CircRNA biogenesis.
Fig. 2: CircRNA degradation and exosome release.
Fig. 3: CircRNA functions.

Change history

  • 31 August 2021

    The formatting of Anton Jan van Zonneveld’s name in the xml was incorrect, resulting in Jan being wrongly classed as part of his surname. This has now been corrected online.

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All authors wrote the article. J.M.L. researched the data and reviewed or edited the manuscript before submission. Correspondence regarding this Review should be sent to J.M.L. at johan.lorenzen@uzh.ch or j.m.lorenzen@gmail.com.

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Correspondence to Johan M. Lorenzen.

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Nature Reviews Nephrology thanks R.-U. Müller, who co-reviewed with M. Ignarski, X.-M. Meng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Intergenic

Region between two protein-coding genes.

Intragenic

Region within a gene.

Intronic

Intron region of a protein-coding gene.

Alu elements

Short stretches of DNA that contain an abundance of transposable elements.

Rolling circle amplification

An isothermal enzymatic process in which a short DNA or RNA primer is amplified to form a long single-stranded DNA or RNA using a circular DNA template and special DNA or RNA polymerases.

Pyroptosis

A highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response.

Enriched terms

Gene ontology term enrichment is a technique for interpreting sets of genes that makes use of the gene ontology system of classification, in which genes are assigned to a set of predefined bins on the basis of their functional characteristics.

Endothelial to mesenchymal transition

(EndoMT). A process in which an endothelial cell undergoes a series of molecular events that lead to a change in phenotype towards a mesenchymal cell such as a myofibroblast or smooth muscle cell.

Aptamers

Oligonucleotide or peptide molecules that bind to a specific target molecule.

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van Zonneveld, A.J., Kölling, M., Bijkerk, R. et al. Circular RNAs in kidney disease and cancer. Nat Rev Nephrol 17, 814–826 (2021). https://doi.org/10.1038/s41581-021-00465-9

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