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Am J Physiol Gastrointest Liver Physiol 297: G726-G734, 2009. First published July 23, 2009; doi:10.1152/ajpgi.00162.2009
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LIVER AND BILIARY TRACT

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Jordi Colmenero,1 Ramón Bataller,1 Pau Sancho-Bru,1 Marlene Domínguez,1 Montserrat Moreno,1 Xavier Forns,1 Miquel Bruguera,1 Vicente Arroyo,1 David A. Brenner,2 and Pere Ginès1

1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and 2University of California San Diego School of Medicine, La Jolla, California

Submitted April 28, 2009 ; accepted in final form July 17, 2009

Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen {alpha}1(I) and {alpha}1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.

angiotensin; liver fibrosis; antifibrogenic


Address for reprint requests and other correspondence: R. Bataller, Liver Unit, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain (e-mail: bataller{at}clinic.ub.es).






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