CircRNA_33702 Promotes Renal Fibrosis by Targeting the miR-29b-3p/WNT1-Inducible Signaling Pathway Protein 1 Pathway
pubmed: wnt1 2023-01-25
J Pharmacol Exp Ther. 2023 Jan;384(1):61-71. doi: 10.1124/jpet.122.001280. Epub 2022 Sep 24.
Growing evidence suggest that circular RNAs (circRNAs) are critical mediators in renal diseases. However, there have been very few reports about the role of circRNAs in renal fibrosis. In this study, circRNA_33702 was found to be upregulated, both in unilateral ureteral obstruction (UUO) mice and in TGF-β1-treated Boston University mouse proximal tubule cells. Furthermore, hsa_circ_0026331, homologous with mmu_circ_33702, was found to be upregulated in TGF-β1-treated HK-2 cells. Although knockdown of circRNA_33702 or hsa_circ_0026331 was shown to relieve the TGF-β1-induced expression of collagen I, collagen III, and fibronectin, overexpression of circRNA_33702 was found to exert an inhibitory effect on the expression of the same genes. Mechanistically, circRNA_33702 was demonstrated to bind directly with miR-29b-3p and inhibit its expression. MiR-29b-3p mimic was shown to inhibit the TGF-β1-induced expression of collagen I, collagen III, and fibronectin. Moreover, WNT1-inducible signaling pathway protein 1 (WISP1) was identified as a target of miR-29b-3p, and the expression of WISP1 was observed to be repressed by miR-29b-3p. Notably, knockdown of circRNA_33702 was found to attenuate the expression of collagen I, collagen III, and fibronectin by inhibiting the expression of WISP1, and the observed inhibitory effect can be reversed by miR-29b-3p inhibitor. Finally, inhibition of circRNA_33702 was shown to attenuate interstitial fibrosis in UUO mice via the miR-29b-3p/WISP1 axis. In general, our data show that circRNA_33702 may promote renal fibrosis via the miR-29b-3p/WISP1 axis, which may potentially be developed as a new therapeutic target. SIGNIFICANCE STATEMENT: This study's findings suggested that circRNA_33702 plays a profibrosis role and that circRNA_33702 with the homologous human hsa_circ_0026331 may be a novel therapeutic target of renal fibrosis.