0052: Role of kinins in diabetic wound healing

Abstract

The diabetic foot is associated with pain, decrease in patient's quality of life, considerable costs, and amputation. In this study, we determined the role of KKS, via activation of bradykinin receptors (B1R or B2R), in a mouse model of diabetic wound healing. Diabetic or nondiabetic mice are wounded with an 8-mm punch biopsy and then are treated or not with specific B1R or B2R agonists (720nmol/kg.d -1 ) and/or B2R antagonist (Icatibant, 500μg/kg.dg/d -1 ). The wound-healing surface was daily followed up. At 11 days, the scar were analysed by histology (Masson's trichrome staining) and B1R and B2R expression were assessed (RT-qPCR). Effects of the agonists on cells (fibroblasts and keratinocytes) migration and proliferation were also analysed. In diabetic condition, mRNA of B1R and B2R was increased in skin (p<0.01). B1R activation had no effect on wound closure in our model. In contrast, B2R activation dramatically delayed wound healing in diabetic (p<0.001) or nondiabetic (p<0.01) mice. Histological analysis of scar showed significant skin disorganization and epidermis thickening with B2R agonist (p<0.05). In vitro, B2R agonist induced an increase of keratinocyte proliferation (+46% after 48h, p<0.01) and a stimulation of keratinocyte migration (+30% after 24h, p<0.05). These effects was associated with ERK phosphorylation which occurs downstream of EGFR activation (p<0.05). B2R agonist had no effect on fibroblast migration but decreased fibroblast proliferation (–33% after 48h, p<0.05). Co-treatment with Icatibant abrogated in vivo and in vitro effects observed with B2R agonist. Moreover, Icatibant alone hastened wound healing and decrease the epidermis thickening induced by diabetes. In conclusion, KKS, through the B2R but not the B1R, plays a critical role in proliferation and remodelling phases of skin wound healing in mice. While more studies are needed, Icatibant could be used to correct the diabetic wound healing defect.