Knockdown of circ_0003928 ameliorates high glucose-induced dysfunction of human tubular epithelial cells through the miR-506-3p/HDAC4 pathway in diabetic nephropathy

Abstract

Background Previous data have indicated the importance of circular RNA (circRNA) in the pathogenesis of diabetic nephropathy (DN). The study is designed to investigate the effects of circ_0003928 on oxidative stress and apoptosis of high glucose (HG)-treated human tubular epithelial cells (HK-2) and the underlying mechanism. Methods The DN cell model was established by inducing HK-2 cells using 30 mmol/L D-glucose. RNA expression of circ_0003928, miR-506-3p and histone deacetylase 4 (HDAC4) was detected by quantitative real-time polymerase chain reaction. Cell viability and proliferation were investigated by cell counting kit-8 and 5-Ethynyl-29-deoxyuridine (EdU) assays, respectively. Oxidative stress was evaluated by commercial kits. Caspase 3 activity and cell apoptotic rate were assessed by a caspase 3 activity assay and flow cytometry analysis, respectively. Protein expression was detected by Western blotting analysis. The interactions among circ_0003928, miR-506-3p and HDAC4 were identified by dual-luciferase reporter and RNA pull-down assays. Results Circ_0003928 and HDAC4 expression were significantly upregulated, while miR-506-3p was downregulated in the serum of DN patients and HG-induced HK-2 cells. HG treatment inhibited HK-2 cell proliferation, but induced oxidative stress and cell apoptosis; however, these effects were reversed after circ_0003928 depletion. Circ_0003928 acted as a miR-506-3p sponge, and HDAC4 was identified as a target gene of miR-506-3p. Moreover, the circ_0003928/miR-506-3p/HDAC4 axis regulated HG-induced HK-2 cell dysfunction. Conclusion Circ_0003928 acted as a sponge for miR-506-3p to regulate HG-induced oxidative stress and apoptosis of HK-2 cells through HDAC4, which suggested that circ_0003928 might be helpful in the therapy of DN.

Circ_0068087 knockdown attenuates high‐glucose‐induced human tubular epithelial cell injury in a microribonucleic acid/progestin and adipoQ receptor 3‐dependent manner in diabetic nephropathy

“…Considerable studies show the vital role of circRNA in multiple diseases, including DN 14 . Furthermore, some studies focus on the therapeutic potential of circRNAs in DN, such as circ_0000712 31 and circ_0003928 32 . Currently, there is no research regarding circ_0068087 in renal tubular cell injury during DN.…”

The role of circular RNA in Diabetic Nephropathy

“…Knockout of CIRC_0003928 through miR-506-3p/HDAC4 pathway can improve the proliferation, apoptosis and oxidative stress of RTECs induced by DKD high glucose. It also suggests that CIRC_0003928 may be a potential therapeutic target for DKD [41]. Circ_0000064 is the sponge of miR-532-3P, ROCK1 is the target of miR-532-3p, and its expression is suppressed by Circ_0000064 gene knockout.…”