Angiotensinogen is encoded by the gene AGT and is a glycoprotein secreted by hepatocytes that is cleaved renin to yield angiotensin I, which is further cleaved to generate angiotensin II.
Angiotensinogen is is the precursor of angiotensin peptides, which are members of the renin-angiotensin system that play a critical role in the origins of hypertension.
Angiotensinogen is the rate limiting factor in the production of angiotensin II and links angiotensinogen and angiotensin II to hypertension.
Angiotensinogen concentrations in the circulation correlates with blood pressure in primary hypertension.
The greater the copy of the angiotensinogen gene, the higher the blood pressure.
Plasma angiotensinogen levels correlate with blood pressure in hypertension and its overexpression is a hallmark of hypertension with endothelial dysfunction, cardiac hypertrophy and renal abnormalities.
Angiotensinogen is the most proximal component of the angiotensin system.
Circulating angiotensinogen is derived primarily from the liver.
Blood pressure is proportional to the levels of angiotensinogen in the circulation that determine the final amounts of angiotensin II generated by the renin-angiotensin system.
Zilebesiran is a siRNA that targets the AGT gene in the liver and post-transcriptionally silences its expression leading to a decreased production of angiotensinigen protein, suppressed synthesis of angiotensin I, and angiotensin II and consequently blood pressure lowering.
Zilebesiran reduces hepatic angiotensinogen messenger RNA, resulting in reduction of angiotensinogen synthesis.
Zilebesiran given is a single subcutaneous dose of 200 mg or more induced dose dependent reductions in serum angiotensinogen and ambulatory blood pressure that is sustained for up to 24 weeks.