Circular RNA-VPS13A attenuates diabetes-induced enteric glia damage by targeting miR-182/GDNF Axis

Gastrointestinal (GI) complications of diabetes mellitus (DM) significantly impact on patients' quality of life. Enteric glial cells (EGC) are the key cell type of enteric nervous system (ENS), which contributes to the destruction of gut homeostasis in DM. Circular RNAs (circRNAs) are a novel type of RNAs abundant in the eukaryotic transcriptome, which form covalently closed continuous loops. In this study, the contribution of circRNAs to EGC damage in DM is investigated. Transcriptome sequencing analysis and functional study show that circVPS13A is significantly down-regulated in hyperglycemia-treated EGC, and circVPS13A overexpression attenuates EGC damage in both in vitro and in vivo DM models. In vitro mechanistic study using dual-luciferase reporter assay, affinity-isolation assay, fluorescence in situ hybridization (FISH) and immunostaining analysis identify that circVPS13A exerts its protective effect by sponging miR-182 and then up-regulates glial cell line-derived neurotrophic factor (GDNF) expression. In addition, in vivo study confirms that the circVPS13A-miR-182-GDNF network regulation can attenuate hyperglycemia-induced EGC damage of duodenum in streptozotocine (STZ)-induced DM mice. The findings of this study may provide novel insights into the protective role of circVPS13A in DM-associated EGC damage and clues for the development of new therapeutic approaches for the prevention of GI complications of DM.