Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
Article first published online: 20 DEC 2012
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Endothelin. Guest Editors: Anthony P Davenport and Matthias Barton
Volume 168, Issue 2, pages 389–402, January 2013
How to Cite
Marcon, R., Claudino, R., Dutra, R., Bento, A., Schmidt, E., Bouzon, Z., Sordi, R., Morais, R., Pesquero, J. and Calixto, J. (2013), Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis. British Journal of Pharmacology, 168: 389–402. doi: 10.1111/j.1476-5381.2012.02136.x
- Issue published online: 20 DEC 2012
- Article first published online: 20 DEC 2012
- Accepted manuscript online: 13 AUG 2012 06:51AM EST
- Manuscript Accepted: 2 AUG 2012
- Manuscript Revised: 20 JUL 2012
- Manuscript Received: 5 MAR 2012
- kinin B1 and B2 receptors;
- DSS-induced colitis;
- tight junction;
Background and Purpose
Kinins are pro-inflammatory peptides that are released during tissue injury, including that caused by inflammatory bowel disease. Herein, we assessed the role and underlying mechanisms through which the absence of kinin B1 receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice.
B1 and B2 receptor antagonists and B1 receptor knockout mice (B1−/−) were used to assess the involvement of B1 and B2 receptor signalling in a DSS-colitis. B1 receptor, B2 receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type (WT) and B1−/− mice.
DSS-induced colitis was significantly exacerbated in B1−/− compared with WT mice. IL-1β, IFN-γ, keratinocyte-derived chemokine and macrophage inflammatory protein-2 were markedly increased in the colon from DSS-treated B1−/− compared with DSS-treated WT mice. Treatment of WT mice with a selective B1 receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B2 receptor mRNA expression was significantly up-regulated in colonic tissue from the B1−/− mice after DSS administration. Moreover, treatment with a selective B2 receptor antagonist prevented the exacerbation of colitis in B1−/− mice following DSS administration. The water- or DSS-treated B1−/− mice showed a decrease in occludin gene expression, which was partially prevented by the B2 receptor antagonist.
Conclusions and Implications
A loss of B1 receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1−/− may be associated with compensatory overexpression of B2 receptors, which, in turn, modulates tight junction expression.