title: 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.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France.
authors.forename: Dorinne
authors.initials: D
authors.lastname: Desposito
authors.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chollet
authors.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France.
authors.forename: Christopher
authors.initials: C
authors.lastname: Taveau
authors.affiliation: INSERM U 976, Denis Diderot University, Paris, France Dermatology Department, Bichat Hospital, AP-HP, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Descamps
authors.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.affiliation: 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.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France nadine.bouby@crc.jussieu.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bouby
authors.affiliation: INSERM U 1138, Cordeliers Research Center, 75006 Paris, France Paris Descartes University, 75006 Paris, France Pierre et Marie Curie University, 75005 Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Waeckel
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012883:Skin Ulcer / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha; C583125:bradykinin, (Hyp(3)-Thi(5)-(N)Chg(7)-Thi(8))-bradykinin; D001920:Bradykinin
keywords: Type 1 diabetes; Type 2 diabetes; bradykinin receptors; kallikrein–kinin system; skin wound healing