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Peer-reviewedCC BY-NC-NDJournal of translational medicine

Angiotensinogen as a molecular hub in interorgan communication.

  • Jianan Zhou1,2,3,4,5
  • Ximing Ye1,2,3,4,5
  • Yuying Wang1,2,3,4,5
  • Min Hong1,2,3,4,5
  • Jiabing Rong6,7,8,9,10
  • Jianan Wang11,12,13,14,15
  • Yinchuan Xu16,17,18,19,20
20 affiliations
  1. 1Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  2. 2State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.
  3. 3Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China.
  4. 4Transvascular Implantation Devices Research Institute, Hangzhou, China.
  5. 5Binjiang Institute of Zhejiang University, Hangzhou, China.
  6. 6Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. [email protected].
  7. 7State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China. [email protected].
  8. 8Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China. [email protected].
  9. 9Transvascular Implantation Devices Research Institute, Hangzhou, China. [email protected].
  10. 10Binjiang Institute of Zhejiang University, Hangzhou, China. [email protected].
  11. 11Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. [email protected].
  12. 12State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China. [email protected].
  13. 13Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China. [email protected].
  14. 14Transvascular Implantation Devices Research Institute, Hangzhou, China. [email protected].
  15. 15Binjiang Institute of Zhejiang University, Hangzhou, China. [email protected].
  16. 16Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. [email protected].
  17. 17State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China. [email protected].
  18. 18Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China. [email protected].
  19. 19Transvascular Implantation Devices Research Institute, Hangzhou, China. [email protected].
  20. 20Binjiang Institute of Zhejiang University, Hangzhou, China. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhou2026angiotensinogen,
  title = {{Angiotensinogen as a molecular hub in interorgan communication.}},
  author = {Jianan Zhou and Ximing Ye and Yuying Wang and Min Hong and Jiabing Rong and Jianan Wang and Yinchuan Xu},
  journal = {Journal of translational medicine},
  year = {2026},
  month = oct,
  doi = {10.1186/s12967-026-09074-1},
  url = {https://europepmc.org/article/MED/42958536},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Angiotensinogen as a molecular hub in interorgan communication.
AU  - Jianan Zhou
AU  - Ximing Ye
AU  - Yuying Wang
AU  - Min Hong
AU  - Jiabing Rong
AU  - Jianan Wang
AU  - Yinchuan Xu
PY  - 2026
DA  - 2026/10/21
JO  - Journal of translational medicine
DO  - 10.1186/s12967-026-09074-1
UR  - https://europepmc.org/article/MED/42958536
AB  - 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.
SN  - 1479-5876
ER  -