Renal Tubular Epithelial Cell-Derived hsa_circ_0008925 From Urine Is Related to Chronic Renal Fibrosis

Abstract

Renal fibrosis (RF) is a crucial pathological factor in the progression of chronic kidney disease (CKD) to end-stage renal failure, and accurate and noninvasive assays to monitor the progression of renal fibrosis are needed. Circular RNAs (circRNAs) are noncoding RNAs that can be used as diagnostic biomarkers and therapeutic targets for human diseases. In this study, we analysed the expression of hsa_circ_0008925 in human urinary renal tubular cells and investigated its role in renal fibrosis. Urinary samples were collected from CKD patients with varying degrees of renal fibrosis; renal tubular epithelial cells were isolated from the urinary samples using magnetic bead sorting. In patients with moderate-severe renal fibrosis, the expression of hsa_circ_0008925 in urinary renal tubular epithelial cells was elevated compared to that in patients with no renal fibrosis to mild renal fibrosis. Spearman correlation analysis indicated that the hsa_circ_0008925 expression was positively correlated with serum creatinine (Scr, rs = 0.424, p = 0.031). The expression of hsa_circ_0008925 was elevated in TGF-β1-treated HK-2 cells in vitro. Silencing of hsa_circ_0008925 using siRNA inhibited TGF-β1-induced fibrosis in HK2 cells. RNA pull-down and mass spectrometric analyses indicated that serine/arginine-rich splicing factor 6 (SRSF6) is the downstream of hsa_circ_0008925. Silencing mmu_circ_0002215 and inhibiting SRSF6 alleviated renal fibrosis in a UUO model in vivo. Inhibiting hsa_circ_0008925/SRSF6 alleviated renal fibrosis in vitro and in vivo. These findings suggest that targeting the hsa_circ_0008925/SRSF6 pathway could hold promise as a potential therapeutic strategy for treating renal fibrosis.

Keywords: SRSF6; chronic kidney disease; circRNAs; mechanism; renal fibrosis.