90 EVIDENCE OF A VASOPRESSIN-INDEPENDENT AQP2 EXPRESSION AND WATER RETENTION IN REFRACTORY ASCITES

Abstract

Liver transplantation is the only curative treatment for advanced liver cirrhosis. Therapies aimed at halting the progression of the disease are urgently needed. Previous studies have shown that the administration of recombinant insulin like growth factor-I (IGF-I) induces hepatoprotective effects in experimental cirrhosis. However, the necessity of using high daily doses of the protein for a long period of time makes this therapy very costly hampering their clinical application. As an alternative therapeutic approach, we have evaluated whether sustained IGF-I expression within the liver from viral vectors based on the Simian Virus 40 (rSVIGF-I) could exert therapeutic effects in liver cirrhosis. We have previously shown that intraportal injection of rSVIGF-I in rats prior to the development of liver cirrhosis induces the expression of hepatocyte growth factor (HGF) in the liver and delays the progression of the disease. In the present study we have tested the effect of the vector in rats that had already developed advanced liver cirrhosis. Liver cirrhosis was induced in Sprague-Dawley male rats by intragastric administration of CCl4 for 12 weeks and then a single dose of rSVIGF-I (1011 vp/rat) was administered by different routes. The following administration routes were tested: intraportal (IP), intrahepatic (IH), intraarterial (IA) and intrabiliar (IB). At the end of the study, cirrhotic rats treated with rSVIGF-I showed reduced serum bilirubin, transaminases and liver fibrosis scores as well as increased expression of serum albumin as compared to mock-infected cirrhotic animals. The effects were more prominent in rats treated by IP or IA injection, suggesting that these routes could allow better access of the vector to hepatocytes in fibrotic livers. IGF-I expression correlated with the increase of mRNA levels of IGF-I binding protein 3 (whose synthesis is induced by IGF-I) and with upregulation of HGF, a factor that seems to mediate hepatoprotective effects of IGF-I. These results indicate that established cirrhosis can be reverted by IGF-I and also, that rSVIGF-I are promising vectors for the treatment of this disease.