microRNA-23a-3p prevents the onset of type 2 diabetes mellitus by suppressing the activation of NLRP3 inflammatory bodies-caused pyroptosis through negatively regulating NEK7.
2020
AIMS/INTRODUCTION: microRNAs (miRNAs) possess crucial functions in governing metabolisms associated with type 2 diabetes mellitus (T2DM). This study aims to investigate the role of miR-23a-3p in pyroptosis caused by NLRP3 inflammatory body activation, thereby reducing the occurrence of T2DM. METHODS miR-23a-3p and NEK7 expression in T2DM patients and rat models was examined. Dual luciferase reporter gene experiments were used to verify targeting relationship between miR-23a-3p and NEK7. Bone marrow-derived macrophages (BMDMs) were transfected with miR-23a-3p mimic, miR-23a-3p inhibitor or shNEK7 and were treated with a specific activator of NLRP3 inflammatory body [lipopolysaccharide (LPS) + Adenosine-5'-triphosphate (ATP)] to evaluate expression of NEK7, miR-23a-3p, GSDMD p30, pro-caspase-1 and caspase-1 in cells, and IL-1β and TNF-α in supernatant. T2DM rat models were used to observe the influences of miR-23a-3p, NEK7 and NLRP3 inflammatory body on pyroptosis and T2DM in vivo. RESULTS NEK7 was over-expressed, while miR-23a-3p was under-expressed in patients and rat models with T2DM. NEK7 was a target gene of miR-23a-3p. After the addition of LPS + ATP in BMDMs, the expression of miR-23a-3p subsequently declined. Moreover, the addition of LPS + ATP elevated NEK7, NLRP3, pro-caspase-1, cle-caspase-1 and GSDMD p30 expressions in BMDMs, and enhanced levels of IL-1β and TNF-α in the supernatant, accompanied with conspicuous cell pyroptosis, which was reversed after miR-23a-3p overexpression and NEK7 silencing. miR-23a-3p overexpression alleviated liver and kidney damage in T2DM rats and reduced NLRP3-induced pyroptosis. CONCLUSIONS Targeting NEK7 by miR-23a-3p could reduce NLRP3-induced pyroptosis and assuage liver and kidney injuries in T2DM rats.
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