Bradykinin attenuates hepatocellular damage and fibrosis in rats with chronic liver injury.
OBJECTIVE
Recent studies have suggested that the kallikrein-kinin system regulates tissue fibrogenesis. We hypothesize that bradykinin (BK), the main effector peptide of this system, regulates hepatic fibrogenesis.


METHODS
Kallikrein-kinin system components were studied by quantitative reverse-transcription polymerase chain reaction analysis, immunohistochemistry, and Western blotting. The effect of bradykinin on liver injury was studied by infusing saline or bradykinin (1 and 100 ng/kg/min) through a subcutaneous pump into carbon tetrachloride-treated rats and mice treated with Fas-stimulating antibody. Bradykinin effects were studied in cultured hepatic stellate cells (HSCs) and hepatocytes.


RESULTS
Bradykinin receptors and kallikrein-1 were detected in both normal and fibrotic human livers and HSCs. BK receptors were up-regulated in fibrotic livers and activated HSCs. Bradykinin infusion reduced liver damage, as indicated by decreased aminotransferase serum levels and reduced histologic necroinflammatory score without inducing changes in arterial pressure. Moreover, bradykinin attenuated hepatic fibrosis, as indicated by reduced collagen accumulation, smooth muscle alpha-actin content, as well as decreased pro-collagen-alpha1(I) and transforming growth factor-beta1 gene expression. Bradykinin infusion reduced hepatocellular apoptosis induced by anti-Fas-receptor antibody. HSCs responded to bradykinin with intracellular calcium mobilization. Bradykinin reduced procollagen-alpha1(I) and transforming growth factor-beta1 gene expression and induced matrix metalloproteinase-2 activation. Finally, BK induced prosurvival and proliferative intracellular signaling in primary hepatocytes.


CONCLUSIONS
Bradykinin attenuates liver damage and fibrosis development in a rat model of chronic liver injury. Therefore, activation of the kallikrein-kinin system may be a new therapeutic approach to the management of chronic liver disease.
Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Barcelona, Catalonia, Spain.
Pau
P
Sancho-Bru
Ramón
R
Bataller
Guillermo
G
Fernandez-Varo
Montserrat
M
Moreno
Leandra N
LN
Ramalho
Jordi
J
Colmenero
Montserrat
M
Marí
Joan
J
Clària
Wladimiro
W
Jiménez
Vicente
V
Arroyo
David A
DA
Brenner
Pere
P
Ginès
D000818:Animals; D001920:Bradykinin / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006801:Humans; D016234:Kallikrein-Kinin System / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D001920:Bradykinin