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Angiotensinogen is a protein and hormone precursor involved in the renin-angiotensin-aldosterone system (RAAS), which causes an increase in blood pressure. It is produced in the liver and secreted into the bloodstream, where it acts as the substrate for the enzyme renin. It is a serum alpha-2 globulin, which is a type of globular protein that is found in the bloodstream and is usually polar. Unlike other proteins in this category, angiotensinogen does not have an inhibitory affect on other enzymes.
The first step of the RAAS occurs when renin, an enzyme produced in the kidneys and secreted into the bloodstream, binds to angiotensinogen and cleaves it to yield angiotensin I (AI). Although angiotensinogen has upwards of 450 amino acids, depending on the species, only the first 12 on the nitrogen terminal (N-terminal) end are important in the pathway. Only the first 10 are removed by renin to form AI.
The next step in the RAAS occurs when angiotensin-converting enzyme (ACE) cleaves two amino acids from the carbon terminal (C-terminal) end of AI to form angiotensin II (AII), an eight-amino-acid peptide. While AI and angiotensinogen have little to no effect on the body, AII stimulates thirst in the brain, increases blood pressure by constricting blood vessels, and signals the release of vasopressin and aldosterone. Vasopressin increases water retention in the kidneys, while aldosterone increases salt retention there. Both increase the volume of fluid in the bloodstream and raise the blood pressure.
AII is further cleaved to form angiotensin III (AIII), a seven-amino-acid peptide, and later angiotensin IV (AIV), a six-amino-acid peptide, by various angiotensinase enzymes in the blood. AIII and AIV both have similar effects in the body as AII, but are less potent. As a result, they are important in the breakdown of AII and the termination of the RAAS.
Before being broken down, AII also provides positive feedback, increasing the production of angiotensinogen in the liver. Other hormones and molecules that increase production include estrogen, hormones produced by the thyroid, and plasma corticosteroid. Variance in estrogen and AII levels in the blood can also create a change in blood pressure that fluctuates with a woman’s menstrual cycle. Aldosterone levels usually increase during the luteal phase of the cycle, which could exacerbate symptoms of fluid retention and bloating.
The RAAS has been a key interest in the study of hypertension. Angiotensinogen is the pathway’s precursor molecule and renin substrate, so studies have focused on it as a potential indicator of hypertension. Scientists have found strong links between essential hypertension and the angiotensinogen gene for the majority of ethnicities. Chinese, however, have not been found to experience this connection.