MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice
Liu XS, Fan B, Szalad A, Jia L, Wang L, Wang X, Pan W, Zhang L, Zhang R, Hu J, Zhang XM, Chopp M, and Zhang ZG. MicroRNA-146a mimics reduce the peripheral neuropathy in type ii diabetic mice. Diabetes 2017; 66(12):3111-3121.
MicroRNA-146a (miR-146a) regulates multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. We found that mice (db/db) with type 2 diabetes exhibited substantial downregulation of miR-146a in sciatic nerve tissue. Systemic administration of miR-146a mimics to diabetic mice elevated miR-146a levels in plasma and sciatic nerve tissue and substantially increased motor and sensory nerve conduction velocities by 29 and 11%, respectively, and regional blood flow by 50% in sciatic nerve tissue. Treatment with miR-146a mimics also considerably decreased the response in db/db mice to thermal stimuli thresholds. Histopathological analysis showed that miR-146a mimics markedly augmented the density of fluorescein isothiocyanate-dextran-perfused blood vessels and increased the number of intraepidermal nerve fibers, myelin thickness, and axonal diameters of sciatic nerves. In addition, miR-146a treatment reduced and increased classically and alternatively activated macrophage phenotype markers, respectively. Analysis of miRNA target array revealed that miR-146a mimics greatly suppressed expression of many proinflammatory genes and downstream related cytokines. Collectively, our data indicate that treatment of diabetic mice with miR-146a mimics robustly reduces DPN and that suppression of hyperglycemia-induced proinflammatory genes by miR-146a mimics may underlie its therapeutic effect.
Medical Subject Headings
Animals; Cytokines; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Interleukin-1 Receptor-Associated Kinases; Macrophage Activation; Male; Mice; MicroRNAs; Myelin Sheath; NF-kappa B; Regional Blood Flow; Sciatic Nerve; TNF Receptor-Associated Factor 6