Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C.
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 alpha1(I) and alpha1(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.
Colmenero
Jordi
J
Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Catalonia, Spain.
Bataller
Ramón
R
Sancho-Bru
Pau
P
Domínguez
Marlene
M
Moreno
Montserrat
M
Forns
Xavier
X
Bruguera
Miquel
M
Arroyo
Vicente
V
Brenner
David A
DA
Ginès
Pere
P
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001707:Biopsy, Needle; D003094:Collagen / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000821:virology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000821:virology; D019808:Losartan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D047228:Angiotensin II Type 1 Receptor Blockers; D018836:Inflammation Mediators; C476420:NOXA1 protein, human; C476419:NOXO1 protein, human; C107953:RAC1 protein, human; D003094:Collagen; D019255:NADPH Oxidases; D014568:Urokinase-Type Plasminogen Activator; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020830:rac1 GTP-Binding Protein; D019808:Losartan