Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade.
2015
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 B 1 and B 2 receptors (B 1 R and B 2 R 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 (B 1 R and B 2 R) and antagonist (B 2 R) 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 B 1 R agonist had no effect on wound healing. In contrast, the B 2 R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro , B 2 R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B 2 R antagonist. Interestingly, in the two mouse models of diabetes, the B 2 R 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 B 2 receptor impairs skin wound healing in mice. B 2 R activation occurs in the diabetic skin and delays wound healing. B 2 R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers.
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