STRUCTURE AND REGULATION OF THE ANGIOTENS INOGEN GENE

Angiotensinogen is a glycoprotein synthesized mainly in hepatocytes an d secreted into the circulation. Angiotensinogen is cleaved by the enz yme renin to produce angiotensin I, which is further converted into a vasoconstricting peptide, angiotensin II, the biologically active pept ide of the renin angiotensin system. The concentration of angiotensino gen 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 dir ections 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' flanki ng region multiple regulating elements, as well as the major control e lements, are present. The cloning and sequencing of the angiotensinoge n cDNA demonstrates the similarity of angiotensinogen to various serin e protease inhibitors produced by the liver and was the beginning of s tudies looking for new physiological roles of angiotensinogen, in addi tion to the substrate for renin. The circulating levels of angiotensin ogen are altered in many different physiological and pathological stat es. High levels of this protein are seen in hypercorticism, inflammati on, pregnancy, and contraceptive therapy, and low levels are associate d with adrenal insuficiency and converting enzyme inhibition. These va riations are mostly due to modifications of the hepatic biosynthesis u nder 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 t o changes in the angiotensinogen gene expression.