Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis.
OBJECTIVE
The aim of this study was to investigate whether in the liver, as in other tissues, there is evidence that angiotensin II, acting via the angiotensin II type 1 receptor (AT1-R), plays a role in fibrogenesis.


METHODS
Sprague-Dawley rats were divided into three groups; sham, bile duct ligated (BDL) and BDL + AT1-R antagonist, irbesartan. Real time RT-PCR was utilised to assess gene expression of the AT1 receptor, TGF-beta1 and alpha1 (I) collagen in the liver. TGF-beta1 and alpha1 (I) collagen mRNA expression and localisation were also assessed by in situ hybridisation. TGF-beta1 activity was assessed by using the TGF-beta inducible gene product betaig-h3. Fibrosis was assessed by the Knodell scoring system, tissue hydroxyproline content and picro-sirius red staining.


RESULTS
Real time RT-PCR revealed that there was a 6-fold up-regulation in AT1 receptor expression in BDL animals compared with shams. This was associated with marked increases in TGF-beta1, betaig-h3 and alpha1 (I) collagen gene expression which were attenuated by AT1-RA treatment. However, AT1-RA therapy produced no significant change in liver histology or hydroxyproline content.


CONCLUSIONS
These results suggest that in the liver angiotensin II may play an important role in the fibrogenic response to injury. However, whether treatment with an AT1-RA will be of therapeutic benefit remains to be determined.
Paizis
G
G
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre Melbourne, Australia. gpaizis@austin.unimelb.edu.au
Gilbert
R E
RE
Cooper
M E
ME
Murthi
P
P
Schembri
J M
JM
Wu
L L
LL
Rumble
J R
JR
Kelly
D J
DJ
Tikellis
C
C
Cox
A
A
Smallwood
R A
RA
Angus
P W
PW
D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D003094:Collagen / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000032:analysis
D057911:Angiotensin Receptor Antagonists; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003094:Collagen