MicroRNAs (miRNAs) are small, noncoding, regulatory RNAs.
12 Since their discovery in 1993, miRNAs have been proven to be an important mechanism of fine-tuning of gene expression
12–15 and play regulatory roles in almost all aspects of normal biological functions
14–34 and diseases.
35 However, roles of miRNAs in DR and its treatment are still largely unknown. Previously, we reported one of the first miRNA transcriptomes of the retina and retinal endothelial cells (RECs) of diabetic rats, and identified a series of miRNAs involved in early DR.
36 Among DR-related miRNAs, we demonstrated that miR-146 is a pivotal negative feedback regulator of nuclear factor kappa-B (NF-κB) activation.
36,37 Nuclear factor kappa-B is a master regulator of inflammatory responses, and plays critical roles in inflammatory damages to RECs and retinal microvasculature during development of DR.
38–44 Nuclear factor kappa-B induces expression of proinflammatory molecules, including intercellular adhesion molecule 1 (ICAM1),
45 a key endothelial adhesion molecule to recruit leukocytes onto endothelial cell surface, and facilitate leukostasis and propagation of inflammatory responses, contributing to REC cell death and DR development.
46–49 We showed that miR-146 inhibited IL-1R/Toll-like receptor (TLR)-mediated NF-κB activation pathway by targeting key adaptor molecules, interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6),
36,50 and prevented IL-1β–induced damage to retinal endothelial barrier function in vitro.
37 Furthermore, we showed that miR-146 also inhibited G protein-coupled receptor (GPCR)-mediated NF-κB activation pathway by targeting a key adaptor molecule, Caspase Recruitment Domain Family, Member 10 (CARD10),
37,51 and decreased thrombin-induced leukocyte adhesion to HRECs in vitro.
37 These data suggest that miR-146 plays an important role in DR through modulating NF-κB activation and inflammatory responses.