ANGIOTENSIN-II AND DEXAMETHASONE REGULATE ANGIOTENSINOGEN MESSENGER-RNA BY DIFFERENT MECHANISMS

Angiotensinogen synthesis and secretion in the liver is regulated by glucocorticoids and angiotensin II. In isolated hepatocytes in suspension culture, both dexamethasone and angiotensin II induced an increase in angiotensinogen mRNA (2.5- and 4-fold, respectively) with half maximal stimulation at 20 and 200 nM, respectively. In a nuclear run on assay, transcription of the angiotensinogen gene in nuclei from hepatocytes exposed to angiotensin II was not significantly different from controls, whereas dexamethasone-pretreatment dramatically stimulated angiotensinogen mRNA synthesis. By inhibition of transcription in hepatocytes, as well as in [P-32]uridine pulse and chase experiments, angiotensin II was shown to stabilize angiotensinogen mRNA, prolonging the intracellular half-life from 83 to 191 min. In polysomal extracts from hepatocytes, a 12 kDa protein could be identified, that binds to a probe of the 3'-untranslated region (UTR) angiotensinogen mRNA. The binding activity of this protein appears to be higher in hepatocytes exposed to angiotensin II, and to have a stabilizing effect on angiotensinogen mRNA. It is proposed that angiotensin II enhances the binding activity of a 12 kDa protein the 3'-UTR of angiotensinogen mRNA, which results in increased stability and transcription of angiotensinogen mRNA.