miR-146a mediates thymosin β4 induced neurovascular remodeling of diabetic peripheral neuropathy in type-II diabetic mice

Brain Res. 2019 Mar 15;1707:198-207. doi: 10.1016/j.brainres.2018.11.039. Epub 2018 Nov 27.


Diabetes induces neurovascular dysfunction leading to peripheral neuropathy. MicroRNAs (miRNAs) affect many biological processes and the development of diabetic peripheral neuropathy. In the present study, we investigated whether thymosin-β4 (Tβ4) ameliorates diabetic peripheral neuropathy and whether miR-146a mediates the effect of Tβ4 on improved neurovascular function. Male Type II diabetic BKS. Cg-m+/+Leprdb/J (db/db) mice at age 20 weeks were treated with Tβ4 for 8 consecutive weeks, and db/db mice treated with saline were used as a control group. Compared to non-diabetic mice, diabetic mice exhibited substantially reduced miR-146a expression, and increased IL-1R-associated kinase-1 (IRAK1), tumor necrosis factor (TNFR)-associated factor 6 (TRAF6) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) activity in sciatic nerve tissues. Treatment of diabetic mice with Tβ4 significantly elevated miR-146a levels and overcame the effect of diabetes on these proteins. Tβ4 treatment substantially improved motor and sensory conduction velocity of the sciatic nerve, which was associated with improvements in sensory function. Tβ4 treatment significantly increased intraepidermal nerve fiber density and augmented local blood flow and the density of fluorescein isothiocyanate (FITC)-dextran perfused vessels in the sciatic nerve tissue. In vitro, treatment of dorsal root ganglion (DRG) neurons and mouse dermal endothelial cells (MDEs) with Tβ4 significantly increased axonal outgrowth and capillary-like tube formation, whereas blocking miR-146a attenuated Tβ4-induced axonal outgrowth and capillary tube formation, respectively. Our data indicate that miR-146a may mediate Tβ4-induced neurovascular remodeling in diabetic mice, by suppressing pro-inflammatory signals.

Keywords: Diabetes; Mice; Peripheral neuropathy; Thymosin β4; miR-146a.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Neuropathies / genetics
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / therapy*
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Ganglia, Spinal / metabolism
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism
  • Neuronal Outgrowth / drug effects
  • Sciatic Nerve / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 6 / metabolism
  • Thymosin / metabolism
  • Thymosin / pharmacology*


  • MicroRNAs
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • TRAF6 protein, mouse
  • thymosin beta(4)
  • Thymosin
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse