miR-146a mediates thymosin ß4 induced neurovascular remodeling of diabetic peripheral neuropathy in type-II diabetic mice.

ABSTRACT

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-ß4 (Tß4) ameliorates diabetic peripheral neuropathy and whether miR-146a mediates the effect of Tß4 on improved neurovascular function. Male Type II diabetic BKS. Cg-m+/+Leprdb/J (db/db) mice at age 20 weeks were treated with Tß4 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 Tß4 significantly elevated miR-146a levels and overcame the effect of diabetes on these proteins. Tß4 treatment substantially improved motor and sensory conduction velocity of the sciatic nerve, which was associated with improvements in sensory function. Tß4 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 Tß4 significantly increased axonal outgrowth and capillary-like tube formation, whereas blocking miR-146a attenuated Tß4-induced axonal outgrowth and capillary tube formation, respectively. Our data indicate that miR-146a may mediate Tß4-induced neurovascular remodeling in diabetic mice, by suppressing pro-inflammatory signals.