AGT (angiotensinogen; HGNC:333, NCBI Gene ID 183) is a human locus mapped to chromosome band 1q42.2 that encodes hepatic non-inhibitory serpin glycoprotein Angiotensinogen (452 mature aa). AGT acts in sole precursor substrate of the Renin-Angiotensin-Aldosterone System (RAAS), together with ACE (Angiotensin-Converting Enzyme Gene), Renin, and Aldosterone. Encodes hepatic angiotensinogen, the sole precursor of angiotensin I and II; targeted by long-acting siRNA therapeutics for hypertension.
Sole precursor substrate of the Renin-Angiotensin-Aldosterone System (RAAS)
Clinical / Therapeutic Role
p.Met235Thr polymorphism in essential hypertension; target of twice-yearly GalNAc-siRNA zilebesiran & antisense oligonucleotides
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 5-exon gene on chromosome 1q42.2 belonging to the serpin superfamily, transcriptionally induced in hepatocytes by glucocorticoids, estrogens, thyroid hormone, angiotensin II, and inflammatory cytokines, with the decapeptide Angiotensin I encoded at the extreme N-terminus (residues 1–10 of the mature protein).
Cellular & Tissue Expression Profile: Synthesized and constitutively secreted into the circulation primarily by hepatic hepatocytes, with local tissue RAAS expression in renal proximal tubules, white adipocytes, and central nervous system astrocytes.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Cleaved specifically at the Leu10-Val11 peptide bond by renal juxtaglomerular renin to release inactive decapeptide Angiotensin I, which is subsequently converted by endothelial angiotensin-converting enzyme (ACE) into octapeptide Angiotensin II—driving systemic arteriolar vasoconstriction, sympathetic outflow, and adrenal zona glomerulosa aldosterone secretion.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations cause severe autosomal recessive renal tubular dysgenesis with neonatal hypotension, whereas the common coding polymorphism p.Met235Thr (rs699, in linkage disequilibrium with the -6G>A promoter variant) elevates plasma angiotensinogen by 15–30% and predisposes to essential hypertension and preeclampsia.
Therapeutic & Clinical Pharmacology: Whereas oral ACE inhibitors and ARBs can trigger compensatory renin escape during incomplete adherence, hepatocyte-targeted GalNAc-conjugated siRNA zilebesiran degrades hepatic AGT mRNA to deplete plasma angiotensinogen by >90%, achieving durable 24-hour blood pressure reductions for up to 6 months after a single subcutaneous injection.