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

• Published in: Journal of diabetes investigation 2021-03, Vol.12 (3), p.334-345
• Main Authors: Chang, Hongye, Chang, Hongjuan, Cheng, Tuanjie, Lee, Garrick D, Chen, Xiaoping, Qi, Kunqing
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animal models; Animals; Apoptosis; ATP; Binding sites; Bone marrow; Caspase; Chromosome 3; Cytokines; Dehydrogenases; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; DNA; Enzymes; Experiments; Female; Humans; Inflammation; Insulin resistance; Kidneys; Kinases; Laboratory animals; Lipopolysaccharides; Liver; LRR‐ and pyrin domain‐containing protein 3; Macrophages; Male; MicroRNAs; MicroRNAs - metabolism; Micro‐ribonucleic acid‐23a‐3p; NIMA-Related Kinases - metabolism; NOD; Oligomerization; Original; Plasmids; Polymerase chain reaction; Proteins; Pyrin Domain; Pyrin protein; Pyroptosis; Rats; Rats, Wistar; Reporter gene; Tumor necrosis factor; Tumor necrosis factor-TNF; Type 2 diabetes mellitus
• ISSN: 2040-1116; 2040-1124
• DOI: 10.1111/jdi.13396

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. Targeting NIMA‐related kinase 7 by micro‐ribonucleic acid could reduce NOD‐, LRR‐ and pyrin domain‐containing protein 3‐induced pyroptosis, and assuage liver and kidney injuries in type 2 diabetes mellitus rats.