Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.
OBJECTIVE
The renin-angiotensin system plays an important role in hepatic fibrogenesis. In other organs, myofibroblasts accumulated in damaged tissues generate angiotensin II, which promotes inflammation and extracellular matrix synthesis. It is unknown whether myofibroblastic hepatic stellate cells, the main hepatic fibrogenic cell type, express the renin-angiotensin system and synthesize angiotensin II. The aim of this study was to investigate whether quiescent and activated human hepatic stellate cells contain the components of the renin-angiotensin system and synthesize angiotensin II.


METHODS
Hepatic stellate cells were freshly isolated from normal human livers (quiescent hepatic stellate cells) and from human cirrhotic livers (in vivo activated hepatic stellate cells). Culture-activated hepatic stellate cells were used after a second passage of quiescent hepatic stellate cells. Angiotensinogen, renin, and angiotensin-converting enzyme were assessed by quantitative polymerase chain reaction. Angiotensin II production was assessed by enzyme-linked immunosorbent assay and immunohistochemistry.


RESULTS
Quiescent hepatic stellate cells barely express the renin-angiotensin system components--angiotensinogen, renin, and angiotensin-converting enzyme--and do not secrete angiotensin II. In contrast, both in vivo activated hepatic stellate cells and culture-activated hepatic stellate cells highly express active renin and angiotensin-converting enzyme and secrete angiotensin II to the culture media. Mature angiotensin II protein is also detected in the cytoplasm of in vivo activated and culture-activated hepatic stellate cells. Growth factors (platelet-derived growth factor and epidermal growth factor) and vasoconstrictor substances (endothelin-1 and thrombin) stimulate angiotensin II synthesis, whereas transforming growth factor-beta and proinflammatory cytokines have no effect. Vasodilator substances markedly attenuate the effect of endothelin-1.


CONCLUSIONS
After activation, human hepatic stellate cells express the components of the renin-angiotensin system and synthesize angiotensin II. These results suggest that locally generated angiotensin II could participate in tissue remodeling in the human liver.
Bataller
Ramón
R
Department of Medicine, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi y Sunyer, University of Brescia School of Medicine, Barcelona, Catalonia, Spain.
Sancho-Bru
Pau
P
Ginès
Pere
P
Lora
José M
JM
Al-Garawi
Amal
A
Solé
Manel
M
Colmenero
Jordi
J
Nicolás
Josep M
JM
Jiménez
Wladimiro
W
Weich
Nadine
N
Gutiérrez-Ramos
José-Carlos
JC
Arroyo
Vicente
V
Rodés
Juan
J
D000804:Angiotensin II / Q000096:biosynthesis* / Q000378:metabolism; D000808:Angiotensinogen / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012084:Renin-Angiotensin System / Q000502:physiology*; D014945:Wound Healing
D012333:RNA, Messenger; D000808:Angiotensinogen; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A