AGT (angiotensinogen) mRNA

Class

RNA interference (siRNA) angiotensinogen-lowering therapeutic

Pathway

Renin-angiotensin-aldosterone system (RAAS) — hepatic angiotensinogen knockdown reducing downstream angiotensin II production

Angiotensinogen (AGT) is a liver-derived protein that serves as the sole precursor substrate for the renin-angiotensin-aldosterone system (RAAS), a hormonal cascade central to blood pressure regulation. Renin cleaves AGT to generate angiotensin I, which is then converted to angiotensin II, a potent vasoconstrictor that also stimulates aldosterone release, sodium retention, and vascular remodeling. Excessive RAAS activity underlies many cases of hypertension and contributes to cardiovascular and kidney disease progression. This mechanism uses small interfering RNA (siRNA) to degrade AGT messenger RNA (mRNA) inside liver cells, reducing the amount of angiotensinogen protein produced at its source. Because AGT sits upstream of every subsequent step in the RAAS cascade, lowering its supply reduces production of both angiotensin I and angiotensin II regardless of how active renin itself becomes. This upstream approach differs from established RAAS blockers, which act on renin, the converting enzyme, or the angiotensin receptor further downstream. Reducing the raw material for the pathway rather than blocking one enzymatic step is intended to produce more complete and sustained suppression of angiotensin II generation. This mechanism is relevant to hypertension, particularly forms that respond incompletely to conventional RAAS-blocking drugs, and to broader cardiovascular and renal conditions where chronic RAAS overactivity drives disease progression.