Angiotensinogen Agt Gene

The human AGT mRNA is encoded from a gene located on chromosome 1, and contains five exons and four introns. The mRNA is 1455 nucleotides long and codes for a globular glycoprotein of 485 amino acids. The coding potential of AGT is located in exons 2 to 5, whereas the first exon encodes only a portion of the 5' untranslated region. Because the Km of renin is close to the plasma concentration of AGT in humans, a modest change in its plasma concentration can affect the rate of ANG II formation. Mouse and rat renin hydrolyze a Leu-Leu bond in mouse and rat AGT, in contrast to the Leu-Val bond in human AGT. Because of this, and perhaps other differences in the AGT protein, the cleavage of AGT by renin is species-specific (12). Mice or rats producing human renin or human AGT, but not both, do not develop hypertension or any other phenotype (13,14).

Experimental evidence suggests that the liver represents the primary source of plasma AGT. AGT is probably not stored in hepatocytes, but is constitutively secreted into the systemic circulation (15). Production of AGT by the liver is regulated by several hormonal factors including estrogen, glucocorticoids, thyroid hormone, insulin, and ANG II (15,16). In accordance with the local-tissue RAS concept, AGT is synthesized in many tissues other than the liver, for example the brain, kidney, heart, adrenal gland, vasculature, and adipose tissue. The AGT produced by these tissues may be converted locally or released into the bloodstream to contribute to the circulating pool of AGT. The production of AGT in these tissues may also be regulated locally, independently of the circulating system. The presence of other components of the RAS, such as renin and ACE necessary for the biosynthesis of active angiotensin peptides in most of the tissues that produce AGT, provides further evidence for the de novo synthesis of ANG II in these tissues (Fig. 1). However, the existence of alternative pathways for the production of ANG II in tissues where some components of RAS were not found cannot be excluded (6).

Fig. 1. Different sites of expression of the components of the renin-angiotensin system (RAS) in the body. The classical systemic RAS in which angiotensinogen (AGT) is derived from the liver, renin from the kidney, and angiotensin-converting enzyme from lung is shown. Presence of different components of the RAS in a variety of tissues has led to the concept of local RAS. AGT expression is also detected in adipose tissue and is induced by obesity in some depots. Adipose tissue is becoming recognized as another potential tissue RAS.

Fig. 1. Different sites of expression of the components of the renin-angiotensin system (RAS) in the body. The classical systemic RAS in which angiotensinogen (AGT) is derived from the liver, renin from the kidney, and angiotensin-converting enzyme from lung is shown. Presence of different components of the RAS in a variety of tissues has led to the concept of local RAS. AGT expression is also detected in adipose tissue and is induced by obesity in some depots. Adipose tissue is becoming recognized as another potential tissue RAS.

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