Improvement of skin wound healing in diabetic mice by kinin B₂ receptor blockade

Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B₁ and B₂ receptors (B₁R and B₂R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B₁R and B₂R) and antagonist (B₂R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1–2-fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B₁R agonist had no effect on wound healing. In contrast, the B₂R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B₂R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B₂R antagonist. Interestingly, in the two mouse models of diabetes, the B₂R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor α) mRNAs. Thus stimulation of kinin B₂ receptor impairs skin wound healing in mice. B₂R activation occurs in the diabetic skin and delays wound healing. B₂R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers.