Ghrelin Promotes Chronic Diabetic Wound Healing by Regulating Keratinocyte Proliferation and Migration Through the ERK1/2 Pathway

Delayed wound healing is a complication of diabetes mellitus and can lead to infection, sepsis, and amputation. Despite the currently available treatments, the global burden of diabetes-related wounds is growing; thus, more effective therapy for diabetic wounds is urgently needed. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is a 28-amino acid peptide hormone. Some reports have confirmed the therapeutic effects of ghrelin on diabetes mellitus and its complications. However, the effects and corresponding mechanisms of ghrelin on chronic diabetic wounds remain unknown. In this study, we explored the effect of ghrelin on diabetic wound healing and investigated the associated mechanisms. We showed that ghrelin accelerated wound healing in diabetic rats by promoting the proliferation and migration of keratinocytes. Re-epithelialization was accelerated in ghrelin-treated wounds, thicker and longer newly formed epidermis and more dividing keratinocytes were observed. We further confirmed that ghrelin regulated keratinocytes by activating the ERK1/2 pathway through its receptor growth hormone secretagogue receptor 1a (GHSR1a). Ghrelin also significantly reduced the levels of pro-inflammatory cytokines and increased the deposition of collagen in diabetic wounds. Our data provides preclinical evidence for the potential application of ghrelin as a compound to promote diabetic wound healing and clarifies the molecular mechanism.