Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones.
The regulation of angiotensinogen gene expression by steroid hormones in the rat liver has been examined. In the intact animal, dexamethasone (7 mg/kg ip) and estradiol (7 mg/kg sc) caused an increase in plasma angiotensinogen, which became first apparent after 5 or 9 h, respectively, and resulted in plasma concentrations 4.6- and 1.9-fold higher than in controls at 24 h. These changes were preceded by comparable increases in hepatic angiotensinogen messenger RNA (mRNA). In contrast, dihydrotestosterone (10 mg/kg sc) failed to alter plasma angiotensinogen, although hepatic angiotensinogen mRNA and total RNA were slightly elevated. In isolated hepatocytes exposed to either dexamethasone or estradiol (10 microM each) angiotensinogen mRNA started to increase within less than 1 or 3 h, respectively, followed, with a further time lag of about 2 h, by an increase in secretion rate of angiotensinogen. Dihydrotestosterone (10 and 100 microM) induced a rapid increase in total hepatocyte RNA (1.3-fold) and angiotensinogen mRNA (2-fold) with a peak at 2 h. Surprisingly, angiotensinogen secretion remained either unaltered (10 microM dihydrotestosterone) or even decreased (100 microM dihydrotestosterone). In a hepatoma cell line (FT02B) and a subclone (Fe 33) stably transfected with the human estrogen receptor, dexamethasone and estradiol induced an increase in angiotensinogen mRNA and secretion with the same characteristics as in hepatocytes. In conclusion, in this study a direct effect of estradiol on angiotensinogen mRNA and secretion in hepatocytes could be established, which differs from that of dexamethasone by a delayed onset of action. The observation, both in vivo and in vitro, that dihydrotestosterone induced an increase in total RNA and angiotensinogen mRNA, which is not accompanied by an increased angiotensinogen secretion, cannot be explained at present. This study also demonstrates the usefulness of a hepatoma cell line stably transfected with the estrogen receptor gene for the investigation of estrogen-dependent effects in vitro.
Klett
C
C
Department of Pharmacology, University of Heidelberg, Germany.
Ganten
D
D
Hellmann
W
W
Kaling
M
M
Ryffel
G U
GU
Weimar-Ehl
T
T
Hackenthal
E
E
D000704:Analysis of Variance; D000808:Angiotensinogen / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014819:Vitellogenins / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014819:Vitellogenins; D013196:Dihydrotestosterone; D000808:Angiotensinogen; D004958:Estradiol; D003907:Dexamethasone; D015500:Chloramphenicol O-Acetyltransferase