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.
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January 2016
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Cover Image
Representative photograph of Massons's trichrome-stained section of an epidermal wound in a mouse with streptozotocin-induced diabetes treated with a kinin B2 receptor antagonist. For further information please see pp. 45-56. Original image courtesy of D. Desposito, C. Chollet, C. Taveau, V. Descamps, F. Alhenc-Gelas, R. Roussel, N. Bouby and L. Waeckel.
Research Article|
November 30 2015
Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade
Dorinne Desposito;
Dorinne Desposito
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
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Catherine Chollet;
Catherine Chollet
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
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Christopher Taveau;
Christopher Taveau
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
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Vincent Descamps;
Vincent Descamps
§INSERM U 976, Denis Diderot University, Paris, France
║Dermatology Department, Bichat Hospital, AP-HP, Paris, France
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François Alhenc-Gelas;
François Alhenc-Gelas
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
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Ronan Roussel;
Ronan Roussel
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
¶Paris Diderot University, 75013 Paris, France
**Diabetology, Endocrinology and Nutrition Department, DHU FIRE, Bichat Hospital, AP-HP, Paris, France
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Nadine Bouby;
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
Correspondence: Dr Nadine Bouby (email [email protected]).
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Ludovic Waeckel
Ludovic Waeckel
*INSERM U 1138, Cordeliers Research Center, 75006 Paris, France
†Paris Descartes University, 75006 Paris, France
‡Pierre et Marie Curie University, 75005 Paris, France
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Publisher: Portland Press Ltd
Received:
April 20 2015
Revision Received:
September 14 2015
Accepted:
October 06 2015
Accepted Manuscript online:
October 06 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (1): 45–56.
Article history
Received:
April 20 2015
Revision Received:
September 14 2015
Accepted:
October 06 2015
Accepted Manuscript online:
October 06 2015
Citation
Dorinne Desposito, Catherine Chollet, Christopher Taveau, Vincent Descamps, François Alhenc-Gelas, Ronan Roussel, Nadine Bouby, Ludovic Waeckel; Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade. Clin Sci (Lond) 1 January 2016; 130 (1): 45–56. doi: https://doi.org/10.1042/CS20150295
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