Sensory neurons mediate diabetic peripheral neuropathy. Using a mouse model of diabetic peripheral neuropathy (BKS.Cg-m+/+Lepr(db)/J (db/db) mice) and cultured dorsal root ganglion (DRG) neurons, the present study showed that hyperglycemia downregulated miR-146a expression and elevated interleukin-1 receptor-activated kinase (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) levels in DRG neurons. In vitro, elevation of miR-146a by miR-146a mimics in DRG neurons increased neuronal survival under high-glucose conditions. Downregulation and elevation of miR-146a in DRG neurons, respectively, were inversely related to IRAK1 and TRAF6 levels. Treatment of diabetic peripheral neuropathy with sildenafil, a phosphodiesterase type 5 inhibitor, augmented miR-146a expression and decreased levels of IRAK1 and TRAF6 in the DRG neurons. In vitro, blockage of miR-146a in DRG neurons abolished the effect of sildenafil on DRG neuron protection and downregulation of IRAK1 and TRAF6 proteins under hyperglycemia. Our data provide the first evidence showing that miR-146a plays an important role in mediating DRG neuron apoptosis under hyperglycemic conditions.
Keywords: 4′,6-diamidino-2-phenylindole; BKS.Cg-m+/+Lepr(db)/J; DAPI; DIG; DRG; HG; IRAK1; LNA; MCID; Micro Computer Imaging Device; NG; OCT; PDE5; RT-PCR; SSC; STZ; TLRs; TRAF6; TUNEL; TdT-mediated dUTP-biotin nick end labeling; a phosphodiesterase type 5; cDNA; complementary DNA; db/db; db/m; diabetes; digoxin; dorsal root ganglion; heterozygote mice; high glucose; interleukin-1 receptor-activated kinase; locked nucleic acid; miRNA; mice; microRNA; mir-146a; normal glucose; optimal cutting temperature; peripheral neuropathy; saline-sodium citrate; sildenafil; streptotozin; toll-like receptors; transcriptase polymerase chain reaction; tumor necrosis factor receptor-associated factor 6.
Published by Elsevier Ltd.