Role Of Agt In Hypertension

The RAS plays an important role in the regulation of BP. The octapeptide, angiotensin II (Ang II), is one of the most active vasopressor agents and is obtained by the proteolytic cleavage of a larger precursor molecule, angiotensinogen (AGT), which is primarily synthesized in the liver and to a lesser extent in the kidney, brain, heart, adrenal, fat, and vascular walls. The human AGT cDNA is 1455 nucleotides long and codes for a 485-amino acid protein (9). AGT is first converted by renin to produce a decapeptide, Ang I, and is then converted to Ang II by the removal of a C-terminal dipeptide by ACE (10). In experimental as well as clinical studies, chronic administration of renin-angiotensin inhibitors has proven effective in lowering BP in hypertension. Genes that encode components of the RAS are therefore potential candidate genes that may play a role in the regulation of BP.

The plasma concentration of AGT is close to the Michaelis constant of the enzymatic reaction between renin and AGT (11). For this reason, a rise in plasma AGT levels can lead to a parallel increase in the formation of Ang II that may ultimately result in hypertension. In fact, recent studies have suggested a direct correlation between AGT and BP. These studies include a highly significant relationship between plasma concentration of AGT and BP in human subjects (4); higher plasma AGT levels in hypertensive subjects and in offspring of hypertensive parents compared with normotensives (12,13); expression of AGT gene in multiple tissues—such as brain, kidney, heart, adrenals, placenta, and vascular walls—that are directly involved in BP regulation (14); elevation of BP in transgenic animals that overexpress AGT gene (7-9); and reduction of BP in AGT gene knockout mice (15). In addition, Kim et al. have introduced up to four copies of the AGT gene in mice, with each copy of the gene resulting in a successive increase in BP (16). These results directly demonstrated that small increases in plasma AGT level can quantitatively influence the fine control of renal vascular resistance and increase BP in a gene dose-dependent manner. A similar ACE gene duplication in mice led to an increase in plasma ACE level but no increase in BP (17), which supports the importance of the AGT gene in human hypertension.

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