Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats

Abstract

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·kg−1·h−1, n = 8), and high dose (UII, 3 nmol·kg−1·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-β ( P < 0.05) and platelet-derived growth factor-β ( 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.

Acute-on-chronic liver failure: the liver and portal haemodynamics

“…Furthermore, urotensin II concentrations correlate with the severity of disease and with portal pressure gradient suggesting that it is likely to be of relevance to the pathology of ACLF [46]. Studies in animal models have shown that infusion of urotensin II into normal rats can promote fibrogenesis, while also increasing portal pressure [47], whereas inhibition of the urotensin II receptor in cirrhotic rats lowered portal pressure, while also increasing splanchnic vascular resistance [48]. Thus, inhibition of urotensin II shows promise as a novel target for therapy of portal haemodynamic derangements in advanced cirrhosis, but clinical studies are awaited.…”

Increased expression of urotensin II and GPR14 in patients with cirrhosis and portal hypertension

“…This phenomenon seems not to be a feature of cirrhosis, but of portal hypertension. Portal hypertension seems to induce vascular and hepatic upregulation of UT and fibrosis, as shown recently by Kemp et al (25). Furthermore, a limitation of our study is that the patients with cirrhosis and portal hypertension are only a fraction of all patients with cirrhosis.…”

Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats

“…patients, suggesting that U-II may play a significant role in the cardiac dysfunction and remodeling associated with this condition (4,12). Our group has demonstrated that U-II infusion in healthy rats can increase portal pressure and induce an increase in hepatic fibrosis (9). However, the direct effects of U-II on the myocardium have not been evaluated extensively.…”

“…hypertrophic modulator, the intracellular mechanism of action of U-II in cardiac cells has not been explored extensively (9,13,15,24,27,29).…”