CircBCL11B acts as a ceRNA to facilitate 1, 2-dichloroethane-induced astrocyte swelling via miR-29b-3p/AQP4 axis in SVG p12 cells. (1st May 2023) - Zhong, Yizhou
Abstract: 1, 2-Dichloroethane (1, 2-DCE) is a pervasive environmental pollutant found in ambient and residential air, as well as ground and drinking water. Brain edema is the primary pathological consequence of 1, 2-DCE overexposure. We found that microRNA (miRNA)-29b dysregulation after 1, 2-DCE exposure can aggravate brain edema by suppressing aquaporin 4 (AQP4). Moreover, circular RNAs (circRNAs) can regulate the expression of downstream target genes through miRNA, and affect protein function. However, circRNAs' role in 1, 2-DCE-induced brain edema via miR-29b-3p/AQP4 axis remains unclear. To address the mechanism's bottleneck, we explored the circRNA-miRNA-mRNA network underlying 1, 2-DCE-driven astrocyte swelling in SVG p12 cells by circRNA sequencing, electron microscopy and isotope 3 H labeling combined with the 3-O-methylglucose uptake method. The results showed that 25 and 50 mM 1, 2-DCE motivated astrocyte swelling, characterized by increased water content, enlarged cell vacuoles, and mitochondrial swelling. This was accompanied by miR-29b-3p downregulation and AQP4 upregulation. We verified that AQP4 were negatively regulated by miR-29b-3p in 1, 2-DCE-induced astrocyte swelling. Also, circRNA sequencing highlighted that circBCL11B was upregulated by 1, 2-DCE. This was manifested as circBCL11B overexpression playing an endogenous competitive role via upregulating AQP4 by binding to miR-29b-3p, thus leading to astrocyte swelling. Conversely, circBCL11B knockdown reversed the 1, 2-DCE-motivated AQP4 upregulation and alleviated the cell swelling. Finally, we demonstrated that the circBCL11B was targeted to miR-29b-3p by fluorescence in situ hybridization and dual-luciferase reporter assay. In conclusion, our findings indicate that circBCL11B acts as a competing endogenous RNA to facilitate 1, 2-DCE-caused astrocyte swelling via miR-29b-3p/AQP4 axis. These observations provide new insight into the epigenetic mechanisms underlying 1, 2-DCE-induced brain edema. Highlights: 1, 2-DCE induces astrocyte swelling by increased water content. 1, 2-DCE induces astrocyte swelling by enlarged cell vacuoles. 1, 2-DCE causes downregulation of miR-29b-3p, upregulation of AQP4 and circBCL11B. AQP4 are negatively regulated by miR-29b-3p in 1, 2-DCE-induced astrocyte swelling. 1, 2-DCE motivates astrocyte swelling via circBCL11B/miR-29b-3p/AQP4 axis.