Overexpression of endothelin-1 in bile duct ligated rats: correlation with activation of hepatic stellate cells and portal pressure.
OBJECTIVE
Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis; although ET-1 is increased in cirrhosis, its pathophysiological role in fibrogenesis and portal hypertension remains controversial. The aim of this study was to investigate splanchnic hemodynamics and to correlate them with changes in ET-1 expression and HSC activation in bile duct ligated (BDL) rats.


RESULTS
Expression of the ET-1 gene was increased early as measured by quantitative reverse transcriptase-polymerase chain reaction (6-fold 3 days after BDL) whereas ET-1 peptide measured by RIA increased significantly only in the late phase (30-fold at 28 days). There was a linear correlation between portal pressure and the amount of ET-1 in the portal vein (r = 0.66; P = 0.003), as well as between ET-1 and the volume fraction of myofibroblasts (r = 0.80, P < 10(-7)) as assessed by morphometry and immunohistochemical staining using alpha-smooth muscle actin.


CONCLUSIONS
During chronic liver injury activation of HSCs and of preproET-1 mRNA is accentuated in the early phase after BDL. The late increase in ET-1 peptide may indicate that this peptide is only secondarily involved in HSC activation. The correlation between ET-1 in portal vein and portal pressure suggests that ET-1 may play an important role in the development of portal hypertension.
Tièche
S
S
Department of Clinical Pharmacology, University of Berne, Switzerland.
De Gottardi
A
A
Kappeler
A
A
Shaw
S
S
Sägesser
H
H
Zimmermann
A
A
Reichen
J
J
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000209:etiology*; D008099:Liver / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes