Micro‐ribonucleic acid‐23a‐3p prevents the onset of type 2 diabetes mellitus by suppressing the activation of nucleotide‐binding oligomerization‐like receptor family pyrin domain containing 3 inflammatory bodies‐caused pyroptosis through negatively regulating NIMA‐related kinase 7
Hongye Chang, Hongjuan Chang, Tuanjie Cheng, Garrick D. Lee, Xiaoping Chen, Kunqing Qi
Abstract
AIMS/INTRODUCTION: Micro-ribonucleic acids (miRNAs) possess crucial functions in governing metabolisms associated with type 2 diabetes mellitus. This study aimed to investigate the role of miR-23a-3p in pyroptosis caused by nucleotide-binding oligomerization-like receptor family pyrin domain containing 3 (NLRP3) inflammatory body activation, thereby reducing the occurrence of type 2 diabetes mellitus. MATERIALS AND METHODS: miR-23a-3p and NIMA-related kinase 7 (NEK7) expression in type 2 diabetes mellitus patients and rat models was examined. Dual-luciferase reporter gene experiments were used to verify the targeting relationship between miR-23a-3p and NEK7. Bone marrow-derived macrophages were transfected with miR-23a-3p mimic, miR-23a-3p inhibitor or short hairpin NEK7 and were treated with a specific activator of NLRP3 inflammatory body (lipopolysaccharide + adenosine-5'-triphosphate) to evaluate expression of NEK7, miR-23a-3p, gasdermin D p30, pro-caspase-1 and caspase-1 in cells, and interleukin-1β and tumor necrosis factor-α in supernatant. Type 2 diabetes mellitus rat models were used to observe the influences of miR-23a-3p, NEK7 and NLRP3 inflammatory body on pyroptosis and type 2 diabetes mellitus in vivo. RESULTS: NEK7 was overexpressed, whereas miR-23a-3p was underexpressed in patients and rat models with type 2 diabetes mellitus. NEK7 was a target gene of miR-23a-3p. After the addition of lipopolysaccharide + adenosine-5'-triphosphate in bone marrow-derived macrophages, the expression of miR-23a-3p subsequently declined. Furthermore, the addition of lipopolysaccharide + adenosine-5'-triphosphate elevated NEK7, NLRP3, pro-caspase-1, cle-caspase-1 and gasdermin D p30 expressions in bone marrow-derived macrophages, and enhanced levels of interleukin-1β and tumor necrosis factor-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 type 2 diabetes mellitus 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 type 2 diabetes mellitus rats.