The renin-angiotensin system in a rat model of hepatic fibrosis: evidence for a protective role of Angiotensin-(1-7).
OBJECTIVE
The circulating renin-angiotensin system (RAS) [plasma renin activity (PRA), Angiotensin (Ang) I, Ang II and Ang-(1-7)] was evaluated in a model of hepatic fibrosis in rats. To investigate the pathophysiological involvement of Ang-(1-7), animals were treated with the Ang-(1-7) Mas receptor antagonist, A-779.


METHODS
RAS components, liver function and histology were examined in male Wistar rats (220-300 g). Animals were submitted to sham-surgery or ligature of the bile duct and evaluated 1, 2, 4 and 6 weeks later. Blood samples were obtained to determine biochemical parameters and RAS components. A second group was treated with A-779 or vehicle to measure liver hydroxyproline and total transforming growth factor beta-1 (TGFbeta1).


RESULTS
PRA and Ang I were significantly elevated in rats at 4 and 6 weeks compared to sham-operated animals. Ang II and Ang-(1-7) progressively increased over the 6 weeks. Changes in RAS profile correlated with histological signs of fibrosis and deterioration in liver function. Pharmacological blockade of the Ang-(1-7) receptor aggravated liver fibrosis with a significant elevation in hydroxyproline and total TGFbeta(1).


CONCLUSIONS
Hepatic fibrosis was associated with RAS activation in our model. Our data also suggested that Ang-(1-7) played a protective role in hepatic fibrosis.
Pereira
Regina Maria
RM
Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Alfredo Balena, 190, Belo Horizonte, MG 30130-100, Brazil.
Dos Santos
Robson Augusto Souza
RA
Teixeira
Mauro Martins
MM
Leite
Virginia Hora Rios
VH
Costa
Lincoln Paiva
LP
da Costa Dias
Filipi Leles
FL
Barcelos
Lucíola S
LS
Collares
Guilherme Birchal
GB
Simões e Silva
Ana Cristina
AC
D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019610:Cytoprotection; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D012084:Renin-Angiotensin System; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C092006:7-Ala-angiotensin (1-7); D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7); D006909:Hydroxyproline