Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice.
OBJECTIVE
Pharmacological blockade of the renin-angiotensin system (RAS) attenuates liver fibrogenesis in rats. Here, we provide genetic evidence implicating angiotensin type 1 (AT1) receptors in liver fibrogenesis.


METHODS
Wild type (WT) and AT1a knockout [AT1a (-/-)] mice were subjected to either sham operation or bile-duct ligation. Fibrosis was assessed by Sirius Red staining and hydroxyproline hepatic content. Fibrogenic and inflammatory cytokines were measured by ELISA.


RESULTS
Bile duct ligation-induced elevation of serum liver enzymes was similar in WT and AT1a (-/-) mice. Bile duct ligated WT mice showed inflammatory changes and severe septal fibrosis. In contrast, AT1a (-/-) mice showed minor fibrotic lesions. Collagen accumulation was lower in AT1a (-/-) mice compared to WT mice. The increase in hepatic concentration of TGFbeta1 and pro-inflammatory cytokines was attenuated in AT1a (-/-) mice compared to WT mice. Immunohistochemistry analysis revealed decreased infiltration by inflammatory cells, lipid peroxidation products as well as decreased phosphorylation of c-Jun and p42/44 MAPK in AT1a (-/-) mice compared to AT1 (+/+) mice.


CONCLUSIONS
AT1 receptors play an important role in the development of fibrosis. Pharmacological blockade of AT1 receptors appears to be a promising approach to treat liver fibrosis.
Yang
Liu
L
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Bataller
Ramón
R
Dulyx
Jennyfer
J
Coffman
Thomas M
TM
Ginès
Pere
P
Rippe
Richard A
RA
Brenner
David A
DA
D000818:Animals; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006505:Hepatitis / Q000097:blood / Q000473:pathology*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000097:blood; D010766:Phosphorylation; D012313:RNA / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1