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

Abstract

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.

• Authors: Dorinne Desposito, Catherine Chollet, Christopher Taveau, Vincent Descamps, François Alhenc-Gelas, Ronan Roussel, Nadine Bouby, Ludovic Waeckel
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 130 Issue 1 Pg. 45-56 (Jan 2016) ISSN: 1470-8736 [Electronic] England
• PMID: 26443866 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Authors; published by Portland Press Limited.

Chemical References

• Bradykinin B2 Receptor Antagonists
• Ccl2 protein, mouse
• Chemokine CCL2
• RNA, Messenger
• Receptor, Bradykinin B2
• Tumor Necrosis Factor-alpha
• bradykinin, (Hyp(3)-Thi(5)-(N)Chg(7)-Thi(8))-bradykinin
• Bradykinin

Topics

• Animals
• Bradykinin (analogs & derivatives, pharmacology)
• Bradykinin B2 Receptor Antagonists (pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chemokine CCL2 (genetics, metabolism)
• Diabetes Complications (drug therapy, etiology, genetics, metabolism, pathology)
• Diabetes Mellitus, Experimental (complications, genetics, metabolism)
• Fibroblasts (drug effects, metabolism, pathology)
• Humans
• Keratinocytes (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NIH 3T3 Cells
• RNA, Messenger (metabolism)
• Receptor, Bradykinin B2 (drug effects, genetics, metabolism)
• Signal Transduction (drug effects)
• Skin (drug effects, metabolism, pathology)
• Skin Ulcer (drug therapy, etiology, metabolism, pathology)
• Time Factors
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Up-Regulation
• Wound Healing (drug effects)