Angiotensinogen as a molecular hub in interorgan communication

Angiotensinogen (AGT) is the sole precursor of angiotensin peptides, its physiological relevance is not determined solely by precursor abundance. Although the liver supplies the bulk of circulating AGT, the protein detected in peripheral tissues may arise from local synthesis, vascular retention, glomerular filtration, barrier crossing, or receptor-mediated uptake. Moreover, the molecular form in which AGT exists carries functional implications: intact AGT and des(Ang I)AGT produce effects that are distinct from—and under certain conditions, opposing to—those of angiotensin II (Ang II). This review repositions AGT as a context-sensitive mediator of interorgan crosstalk, with a clear demarcation between preclinical models and human data. Studies using source-specific knockout and lineage tracing in mice offer the strongest causal evidence for liver-to-kidney AGT trafficking; most other proposed axes lack such granular resolution. Human genetic loss-of-function studies have definitively established AGT’s indispensability for renal morphogenesis and blood-pressure regulation, while observational cohorts and biomarker studies rarely determine its tissue origin or delivery route. Ultimately, the functional output of AGT across organ systems depends on its source, molecular state, local accessibility, enzymatic processing, and the receptor environment. Therapeutic agents that target hepatocytes, such as zilebesiran and tonlamarsen, produce durable AGT suppression and could potentially ease treatment burden relative to conventional daily angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Their slow offset of action, combined with a current lack of solid cardiovascular and renal outcome data, raises an unresolved but critical question: what is the safety margin for AGT reduction before renal self-regulation, fluid–electrolyte balance, or pressor responses to physiological stress become compromised? Overall, AGT does not function as a ubiquitous interorgan signaling molecule; instead, it functions as an upstream determinant whose impact is highly context-dependent, shaped by its site of production, route of dissemination, and mode of processing. This review systematically differentiates experimentally established source-to-target circuits from plausible but as-yet-unconfirmed pathways and outlines the mechanistic and clinical benchmarks that must be met for the safe, tissue-selective application of AGT-targeted therapy.