[Structure and regulation of the expression of the angiotensinogen gene]

Angiotensinogen is a glycoprotein synthesized mainly in hepatocytes and secreted into the circulation. Angiotensinogen is cleaved by the enzyme renin to produce angiotensin I, which is further converted into a vasoconstricting peptide, angiotensin II, the biologically active peptide of the renin angiotensin system. The concentration of angiotensinogen is rate-limiting in the production of angiotensin I and therefore plays an important role in the regulation of angiotensin II production. The development of recombinant DNA technology has introduced new directions for the study of the angiotensinogen molecule. The human, rat and mouse angiotensinogen gene contains five exons interrupted by four intervening sequences and spans 12 kb approximately. In its 5' flanking region multiple regulating elements, as well as the major control elements, are present. The cloning and sequencing of the angiotensinogen cDNA demonstrates the similarity of angiotensinogen to various serine protease inhibitors produced by the liver and was the beginning of studies looking for new physiological roles of angiotensinogen, in addition to the substrate for renin. The circulating levels of angiotensinogen are altered in many different physiological and pathological states. High levels of this protein are seen in hypercorticism, inflammation, pregnancy, and contraceptive therapy, and low levels are associated with adrenal insufficiency and converting enzyme inhibition. These variations are mostly due to modifications of the hepatic biosynthesis under the control of hormonal factors such as glucocorticoid, estrogen, thyroid hormone, insulin and angiotensin II. In addition, it has been found that these changes in the hepatic biosynthesis are due mainly to changes in the angiotensinogen gene expression.