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

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 nondiabetic 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. (C) 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.