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AGT

Official Full Name
angiotensinogen
Organism
Homo sapiens
GeneID
183
Background
The protein encoded by this gene, pre-angiotensinogen or angiotensinogen precursor, is expressed in the liver and is cleaved by the enzyme renin in response to lowered blood pressure. The resulting product, angiotensin I, is then cleaved by angiotensin converting enzyme (ACE) to generate the physiologically active enzyme angiotensin II. The protein is involved in maintaining blood pressure, body fluid and electrolyte homeostasis, and in the pathogenesis of essential hypertension and preeclampsia. Mutations in this gene are associated with susceptibility to essential hypertension, and can cause renal tubular dysgenesis, a severe disorder of renal tubular development. Defects in this gene have also been associated with non-familial structural atrial fibrillation, and inflammatory bowel disease. [provided by RefSeq, Nov 2019]
Synonyms
ANHU; hFLT1; SERPINA8;
Bio Chemical Class
mRNA target
Protein Sequence
MRKRAPQSEMAPAGVSLRATILCLLAWAGLAAGDRVYIHPFHLVIHNESTCEQLAKANAGKPKDPTFIPAPIQAKTSPVDEKALQDQLVLVAAKLDTEDKLRAAMVGMLANFLGFRIYGMHSELWGVVHGATVLSPTAVFGTLASLYLGALDHTADRLQAILGVPWKDKNCTSRLDAHKVLSALQAVQGLLVAQGRADSQAQLLLSTVVGVFTAPGLHLKQPFVQGLALYTPVVLPRSLDFTELDVAAEKIDRFMQAVTGWKTGCSLMGASVDSTLAFNTYVHFQGKMKGFSLLAEPQEFWVDNSTSVSVPMLSGMGTFQHWSDIQDNFSVTQVPFTESACLLLIQPHYASDLDKVEGLTFQQNSLNWMKKLSPRTIHLTMPQLVLQGSYDLQDLLAQAELPAILHTELNLQKLSNDRIRVGEVLNSIFFELEADEREPTESTQQLNKPEVLEVTLNRPFLFAVYDQSATALHFLGRVANPLSTA
Open
Disease
Hypertension
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The essential component of the renin-angiotensin system (RAS), angiotensinogen (AGT) helps to control blood pressure and fluid balance in the body. Its traditional role as the precursor of angiotensin peptides is well known, and new studies have shown other purposes.

Figure 1 describes the traditional and alternative pathways of the renin-angiotensin-aldosterone system, detailing key components and enzymes involved in each pathway.Figure 1. The traditional (right-hand side, orange background) and alternative (left-hand side, blue background) reninangiotensin-aldosterone system pathway. (Larouche-Lebel É, et al., 2021)

AGT Gene and Protein Structure

The human AGT gene produces a 485 amino acid protein with a 33-amino acid signal peptide. The mature AGT protein has 452 amino acids and belongs to the non-inhibitory serine protease inhibitor superfamily. Renin cuts the N-terminal 10 amino acids of AGT to become angiotensin I (AngI), leaving behind a remnant known as des(AngI)AGT. Analysis of crystal structures has revealed several essential properties of the AGT protein:

1. AGT's conformation regulates the disulfide connection between Cys18 and Cys138, potentially regulating the efficacy of renin cleavage across species.

2. The N-terminal area where renin cleaves AGT is obscured in its resting state, necessitating conformational modifications to make it accessible for renin identification.

3. Aside from the eight amino acids that encode AngII, other highly conserved regions within AGT's core serpin domain may be useful in non-AngII-related actions.

AGT's physiological functions

Research on mice with a worldwide AGT deficit reveals low neonatal survival rates, poor growth, renal developmental defects, and hypotension, therefore highlighting AGT's vital function in development and physiological balance. About 90%, of a substantial drop in plasma AGT levels results from liver-specific AGT deletion in mice, proving hepatocytes are the main source of circulating AGT. Additionally showing lower blood pressure, less atherosclerosis, and resistance to diet-induced obesity and hepatic steatosis are these mice. Fascinatingly, AGT generated by adipocytes seems to have little to no impact on blood pressure or obesity but may affect glucose homeostasis and adipose tissue inflammation. Further proof of the liver as the main source of systemic AGT comes from kidney-specific AGT elimination not appreciably influencing plasma AGT levels or blood pressure. Modern methods like AAV-mediated restoration of AGT in hepatocyte-specific AGT-deficient mice have let scientists investigate certain AGT mutations and the functions of des (AngI)AGT.

Phenotypes and Genetic alterations

Mouse genetic research has provided significant new insights into the functions of AGT:

1. Global AGT Deficit: Mice with total AGT deletion exhibit low infant survival rates, poor growth, renal developmental abnormalities, and hypotension, highlighting AGT's crucial role in development and physiological balance.

2. Deletion in cell-specific AGT:  Mice with liver-specific AGT deletion show a significant decrease in plasma AGT levels (about 90%), showing that hepatocytes are the primary source of circulating AGT. These mice exhibit reduced blood pressure, less atherosclerosis, and are resistant to diet-induced obesity and hepatic steatosis.

Contrary to earlier theories, AGT derived from adipocytes seems to have little or no effect on obesity and blood pressure in these animals. It may still have an effect on adipose tissue inflammation and glucose balance, however.

Eliminating AGT, particularly in the kidneys, did not significantly affect plasma AGT levels or blood pressure, confirming the idea that the liver is the primary generator of systemic AGT.

Researchers have used AAV to repopulate AGT in hepatocyte-specific AGT-deficient mice, allowing them to investigate particular AGT mutations and the functions of des (AngI)AGT. Independent of Ang II, these studies have directly shown des (AngI)AGT's role in diet-induced obesity and hepatic steatosis.

Medication Inhibits AGT

Antisense oligonucleotides (ASOs) target AGT and represent a possible treatment approach. AGT ASOs significantly reduce AGT mRNA levels in key organs such as the liver, kidneys, and adipose tissues. This approach has shown potential in decreasing blood pressure, atherosclerosis, and obesity in hypercholesterolemic rats, as well as regulating renal dysfunction in polycystic kidney disease models.

Two pharmaceutical firms, Alnylam and Ionis, are developing AGT ASOs to treat human-resistant hypertension and preeclampsia, respectively. Genetic deletions in multiple RAS components, including renin, ACE, and AT1 receptors, often cause the severe symptoms observed in AGT knockout mice. However, pharmacological inhibition of these factors in adult animals generally has diverse effects.

AGT Morphology and Human Pathophysiology

Several single nucleotide polymorphisms (SNPs) in the AGT gene have been extensively explored, including missense mutations T174M and M235T, as well as promoter region SNPs A(-6)G and A(-20)C. However, the correlations between these polymorphisms and other pathophysiological problems in humans have been unpredictable.

1. M235T Polymorphism: Although this polymorphism has been linked to plasma AGT levels, its relevance with essential hypertension is still debated, depending on the research.

2. Obesity: Plasma AGT concentrations often rise in obese patients, but fall with weight loss. However, variations in AGT expression in adipocytes from both obese and non-obese people have shown conflicting results.

These discrepancies underscore the complex regulation of AGT in human physiology and the need for more study to determine its role in various disorders. Dealing with these difficulties becomes more crucial as AGT becomes a viable therapeutic target for disorders such as hypertension, preeclampsia, and maybe obesity. Future investigations integrating structural biology, genetic alterations, and pharmacological methods will undoubtedly lead to a better understanding of AGT's complex biology and the development of novel therapeutic options for this adaptable protein.

References:

  1. Lu H, Cassis LA, Kooi CW, Daugherty A. Structure and functions of angiotensinogen. Hypertens Res. 2016;39(7):492-500. doi:10.1038/hr.2016.17
  2. Cosarderelioglu C, Nidadavolu LS, George CJ, et al. Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty. Front Neurosci. 2020 Sep 30;14:586314.
  3. Larouche-Lebel É, Loughran KA, Huh T, et al.  Effect of angiotensin receptor blockers and angiotensin converting enzyme 2 on plasma equilibrium angiotensin peptide concentrations in dogs with heart disease. J Vet Intern Med. 2021;35(1):22-32.
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