Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats

Abstract

Background: Wound healing is impaired in diabetes mellitus. The underlying mechanism involved in this process is still unknown. The Akt/mTOR signaling pathway plays a crucial role in the pathogenesis of diabetes.

Objective: we investigated the role of the Akt/mTOR pathway in diabetic wounds and the mechanisms that growth factors activate this pathway to promote diabetic wound healing.

Methods: Full-thickness skin excisional wounds were created on the backs of normal and streptozotocin-induced diabetic rats. The expression of key proteins in the Akt/mTOR pathway was assayed using western blotting; topical effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on diabetic wounds and activation of the Akt/mTOR pathway were subsequently investigated. Activation of the Akt/mTOR pathway by GM-SCF in vitro was examined in rat primary fibroblasts.

Results: The results indicate that the Akt/mTOR pathway was activated in the wound tissue of both non-diabetic and diabetic rats, as indicated by a remarkable increase in expression of total and phosphorylated key proteins in this pathway. However, the expression level of these proteins was dramatically attenuated in diabetic wounds compared with non-diabetic wounds. Upon topical application of GM-CSF, the diabetic wound healing was remarkably improved concomitantly with increased expression and phosphorylation of key proteins in the Akt/mTOR pathway. In addition, rat fibroblast proliferation induced by GM-CSF depended on the Akt/mTOR pathway activation.

Conclusion: Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats. The pharmacologic elevation of this pathway may represent an attractive intervention strategy to improve prognosis of diabetic wounds.

Keywords: Diabetic rats; Fibroblast; Granulocyte-macrophage colony-stimulating factor; Streptozotocin; The Akt/mTOR pathway; Wound healing.