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

Abstract

BACKGROUND AND PURPOSEKinins 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. EXPERIMENTAL APPROACHB1 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. KEY RESULTS DSS-induced colitis was significantly exacerbated in B1-/-compared with WT mice. IL-1b, IFN-g, 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 IMPLICATIONSA 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.

Evidence that kinin B2 receptor expression is upregulated by endothelial overexpression of B1 receptors

“…The present study showed that B 2 R was surprisingly overexpressed in the endothelium of thoracic aorta from TGR(Tie 2 B 1 ) rat. This finding was unexpected since a downregulation should occur as a counter regulatory mechanism for overexpression of B 1 R. It has been reported that the lack of one kinin receptor is compensated by the up-regulation of the other subtype, as shown in the case of deletion of B 2 R [10,12,36] and of B 1 R [16,28].…”

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a b s t r a c tBradykinin (BK) and des-Arg 9 -bradykinin (DBK) of kallikrein-kinin system exert its effects mediated by the B 2 (B 2 R) and B 1 (B 1 R) receptors, respectively. It was already shown that the deletion of kinin B 1 R or of B 2 R induces upregulation of the remaining receptor subtype [10,12,16,28,36]. However studies on overexpression of B 1 R or B 2 R in transgenic animals have supported the importance of the overexpressed receptor but the expression of another receptor subtype has not been determined [17,19,33].

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Bradykinin receptor in immune-mediated renal tubular injury in trichloroethylene-sensitized mice: Impact on NF-κB signaling pathway

“…Research has shown B1R itself is able to induce its own expression through the NF-jB pathway, resulting in the elevation of IL-1b and TNFa synthesis (Marcon et al 2013). Another study indicated that B2R expression could be increased in tandem with increased in NF-jB expression (Ricciardolo et al 2016).…”

“…Increasing evidence has revealed that B1R and B2R expression is involved in the activation of the NF-jB pathway in osteoblasts, fibroblasts, and colonic epithelial cells (Brechter et al 2008;Marcon et al 2013). There are five NF-jB family members in mammalian hosts, e.g.…”

Kinin B1 receptor gene ablation affects hypothalamic CART productionb

“…Interestingly, these authors did not observe changes in the circulating levels of leptin after treatment with kinin B1 receptor antagonist. It has been shown that deletion of one kinin receptor could lead to the modulation of the other kinin receptor expression (Duka et al , 2008 ;Marcon et al , 2013 ). Therefore, the theory could be profered that the kinin B2 receptor could be compensating for the lack of the kinin B1 receptor.…”