Angiopoietin-1/Tie2 signaling pathway contributes to the therapeutic effect of thymosin β4 on diabetic peripheral neuropathy

Angiopoietin-1 (Ang1) and its receptor Tie2 regulate vascular function. Our previous study demonstrated that thymosin beta 4 (T beta 4) ameliorates neurological function of diabetic peripheral neuropathy. Mechanisms underlying the therapeutic effect of T beta 4 on diabetic peripheral neuropathy have not been fully investigated. The present in vivo study investigated whether the Ang1/Tie2 signaling pathway is involved in T beta 4-improved neurovascular remodeling in diabetic peripheral neuropathy. Diabetic BKS. Cg-m+/+Lepr(db)/J (db/db) mice at age 20 weeks were treated with T beta 4 and neutralizing antibody against mouse Tie2 for 4 consecutive weeks. Neurological functional and neurovascular remodeling were measured. Administration of the neutralizing antibody against Tie2 attenuated the therapeutic effect of T beta 4 on improved diabetic peripheral neuropathy as measured by motor and sensory nerve conduction velocity and thermal hypoesthesia compared to diabetic db/db mice treated with T beta 4 only. Histopathological analysis revealed that the neutralizing antibody against Tie2 abolished T beta 4-increased microvascular density in sciatic nerve and intraepidermal nerve fiber density, which were associated with suppression of T beta 4-upregulated occludin expression and T beta 4-reduced protein levels of nuclear factor-kappa B (NF-kappa B) and vascular cell adhesion molecule-1 (VCAM1). Our data provide in vivo evidence that the Ang1/Tie2 pathway contributes to the therapeutic effect of T beta 4 on diabetic peripheral neuropathy. (C) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.