Angiotensin II induces contraction and proliferation of human hepatic stellate cells.
OBJECTIVE
Circulating levels of angiotensin II (ANGII), a powerful vasoconstrictor factor, are frequently increased in chronic liver diseases. In these conditions, hepatic stellate cells (HSCs) proliferate and acquire contractile properties. This study investigated the presence of receptors for ANGII and the effects of ANGII in human HSCs activated in culture.


METHODS
The presence of ANGII receptors was assessed by binding studies. The effects of ANGII on intracellular calcium concentration ([Ca(2+)](i)), cell contraction, and cell proliferation were also assessed.


RESULTS
Binding studies showed the presence of ANGII receptors of the AT1 subtype. ANGII elicited a marked dose-dependent increase in [Ca(2+)](i) and cell contraction. Moreover, ANGII stimulated DNA synthesis and increased cell number. All these effects were totally blocked by losartan and reduced by nitric oxide donors or prostaglandin E(2). The effects of ANGII were barely detectable in quiescent cells (2 days in culture), suggesting that phenotypic transformation of HSCs is associated with a marked increase in the effects of ANGII.


CONCLUSIONS
ANGII induces contraction and is mitogenic for human-activated HSCs by acting through AT1 receptors. These results suggest that activated HSCs are targets of the vasoconstrictor action of ANGII in the intrahepatic circulation.
Bataller
R
R
Liver Unit, Barcelona, Spain.
Ginès
P
P
Nicolás
J M
JM
Görbig
M N
MN
Garcia-Ramallo
E
E
Gasull
X
X
Bosch
J
J
Arroyo
V
V
Rodés
J
J
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008099:Liver / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D019808:Losartan / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012977:Sodium Nitrite / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007457:Iodine Radioisotopes; D020030:Nitric Oxide Donors; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C110881:S-nitro-N-acetylpenicillamine; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D020928:Mitogen-Activated Protein Kinases; D010396:Penicillamine; D019808:Losartan; D015232:Dinoprostone; D012977:Sodium Nitrite; D019331:NG-Nitroarginine Methyl Ester; D013936:Thymidine; D007213:Indomethacin