Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats.
The influence of circulating urotensin II (UII) on liver disease and portal hypertension is unknown. We aimed to evaluate whether UII executes a pathogenetic role in the development of hepatic fibrosis and portal hypertension. UII was administered by continuous infusion over 4 wk in 20 healthy rats divided into three treatment groups, controls (saline, n = 7), low dose (UII, 1 nmol x kg(-1) x h(-1), n = 8), and high dose (UII, 3 nmol x kg(-1) x h(-1), n = 5). Hemodynamic parameters and morphometric quantification of fibrosis were assessed, and profibrotic cytokines and fibrosis markers were assayed in hepatic tissue. UII induced a significant dose-dependent increase in portal venous pressure (5.8 +/- 0.4, 6.4 +/- 0.3, and 7.6 +/- 0.7, respectively, P = 0.03). High-dose UII infusion was associated with an increase in hepatic transcript for transforming growth factor-beta (P < 0.05) and platelet-derived growth factor-beta (P = 0.06). Liver tissue hydroxyproline was elevated in the high-dose group (P < 0.05). No systemic hemodynamic alterations were noted. We concluded that UII infusion elevates portal pressure and induces hepatic fibrosis in normal rats. This response may be mediated via induction of fibrogenic cytokines. These findings have pathophysiological implications in human liver disease where increased plasma UII levels have been observed.
Kemp
William
W
Department of Epidemiology and Preventive Medicine, Monash University, Prahran, Victoria, Australia. w.kemp@alfred.org.au
Kompa
Andrew
A
Phrommintikul
Arintaya
A
Herath
Chandana
C
Zhiyuan
Jia
J
Angus
Peter
P
McLean
Catriona
C
Roberts
Stuart
S
Krum
Henry
H
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000378:metabolism; D006975:Hypertension, Portal / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017082:Portal Pressure / Q000187:drug effects*; D011168:Portal System / Q000187:drug effects* / Q000503:physiopathology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation; D014579:Urotensins / Q000008:administration & dosage / Q000633:toxicity*
D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014579:Urotensins; C029677:urotensin II; D006909:Hydroxyproline