Exacerbation of DSS-induced colitis in mice lacking kinin B(1)  receptors through compensatory up-regulation of kinin B(2)  receptors: the role of tight junctions and intestinal homeostasis.
OBJECTIVE
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 B(1)  receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice.


METHODS
B(1)  and B(2)  receptor antagonists and B(1)  receptor knockout mice (B1(-/-) ) were used to assess the involvement of B(1)  and B(2)  receptor signalling in a DSS-colitis. B(1)  receptor, B(2)  receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type (WT) and B1(-/-)  mice.


RESULTS
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 B(1)  receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B(2)  receptor mRNA expression was significantly up-regulated in colonic tissue from the B1(-/-)  mice after DSS administration. Moreover, treatment with a selective B(2)  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 B(2)  receptor antagonist.


CONCLUSIONS
A loss of B(1)  receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1(-/-)  may be associated with compensatory overexpression of B(2)  receptors, which, in turn, modulates tight junction expression.
Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
R
R
Marcon
R F
RF
Claudino
R C
RC
Dutra
A F
AF
Bento
E C
EC
Schmidt
Z L
ZL
Bouzon
R
R
Sordi
R L T
RL
Morais
J B
JB
Pesquero
J B
JB
Calixto
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004149:Dioxoles / Q000494:pharmacology; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D019108:Tight Junctions / Q000378:metabolism; D015854:Up-Regulation
C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D016207:Cytokines; D004149:Dioxoles; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; C051090:bradykinin, Leu(8)-des-Arg(9)-; C065679:icatibant; D016264:Dextran Sulfate; D009195:Peroxidase; D001920:Bradykinin