The mmu_circRNA_37492/hsa_circ_0012138 function as potential ceRNA to attenuate obstructive renal fibrosis

Xu Cheng,Yinhuai Wang,Lei Yi,Wentao Liu,Kai Ai,Dongshan Zhang,Yijian Li

doi:10.1038/s41419-022-04612-3

Abstract

Circular RNAs (circRNAs) are involved in the pathogenesis of certain renal diseases, however, the function and mechanism of them in renal fibrosis remains largely unknown. In the present study, RNA expression data in unilateral ureteral obstruction (UUO) kidneys was obtained from our previous circRNA Microarray and public Gene Expression Omnibus datasets to construct a ceRNA network. The effects of target circRNA as long as the homologous human circRNA on renal fibrosis was examined in vitro and in vivo. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was further performed among genes regulated by the human circRNA. We found that circRNA_37492, showing well connection degree in the ceRNA network, was abundant expression and high sequence conservation. We observed that the expression of circRNA_37492 was induced by the TGF-β1 or UUO in BUMPT cells and C57BL/6 mice, respectively. In vitro, cytoplasmic circRNA_37492 inhibited type I, III collagen and fibronectin deposition by sponging miR-7682-3p and then upregulated its downstream target Fgb. In vivo, overexpression of circRNA_37492 attenuated fibrotic lesions in the kidneys of UUO mice via targeting miR-7682-3p/Fgb axis. Furthermore, hsa_circ_0012138, homologous with circRNA_37492, may potentially target miR-651-5p/FGB axis in human renal fibrosis. Not only that, GO and KEGG enrichment revealed that hsa_circ_0012138-regulated genes were previously demonstrated to related to the fibrosis. In conclusion, we for the first time demonstrated that circRNA_37492 attenuated renal fibrosis via targeting miR-7682-3p/Fgb axis, and the homologous hsa_circRNA_0012138 was speculated as a possible ceRNA to regulate multiple gene expressions and involve in human renal fibrosis, suggesting that circRNA_37492/hsa_circ_0012138 may serve as potent therapy target for obstructive renal fibrosis disease.

Highlights

Chronic kidney disease (CKD) is a major public health problem with significant morbidity and mortality all over the world, obstructive nephropathy (ON) is the main cause of CKD [1]
Our recent study reported that mmu_circRNA_30032 promoted unilateral ureteral obstruction (UUO)-mice kidney fibrogenesis via microRNA sponge [16], what role the Circular RNA (circRNA) exactly played in renal fibrosis caused by mice-UUO and human ON remains largely unknown
Construction of a circular RNA-associated competing endogenous RNAs (ceRNAs) regulatory network As the flow diagram (Fig. 1A) shows, RNA expression data in UUO kidneys and control samples were obtained from circRNA Microarray and public Gene Expression Omnibus datasets

Summary

INTRODUCTION

Chronic kidney disease (CKD) is a major public health problem with significant morbidity and mortality all over the world, obstructive nephropathy (ON) is the main cause of CKD [1]. Our recent study reported that mmu_circRNA_30032 promoted unilateral ureteral obstruction (UUO)-mice kidney fibrogenesis via microRNA (miRNA) sponge [16], what role the circRNAs exactly played in renal fibrosis caused by mice-UUO and human ON remains largely unknown. To push these results towards clinical use, the homologous circRNA in human was searched out and verified by experiments and bioinformatics. Identification of these circRNAs and their role, may reveal novel therapeutic targets for renal fibrosis caused by ON

RESULTS

Cheng et al 2

DISCUSSION

ETHICS STATEMENT