Angiotensin II Upregulates Angiotensinogen Production Through Feedback Regulation
Angiotensin II, not angiotensin I, upregulates angiotensinogen production through a positive feedback mechanism at the pretranslational level. 1
Mechanism of Angiotensinogen Regulation by Angiotensin II
Angiotensin II exerts a positive feedback effect on the renin-angiotensin-aldosterone system (RAAS) by stimulating hepatic angiotensinogen synthesis. This occurs through several mechanisms:
Pretranslational regulation: Angiotensin II elevates angiotensinogen mRNA concentrations two- to threefold, leading to correspondingly increased angiotensinogen secretion rates after approximately 2 hours 1
mRNA stabilization: Angiotensin II has a stabilizing effect on angiotensinogen mRNA, prolonging its half-life when further synthesis is blocked 1
Intracellular signaling: The effect appears to be mediated through the AT1 receptor, initiating a cascade of intracellular signaling events 2
Evidence for Differential Effects of Angiotensin I vs II
The evidence clearly demonstrates that angiotensin II, not angiotensin I, regulates angiotensinogen:
Direct infusion of angiotensin I (while suppressing plasma renin and angiotensin II production) had no effect on angiotensinogen release rate 3
In contrast, infusion of angiotensin II increased plasma angiotensinogen concentrations 1, 3
This feedback loop appears to be part of a complex regulatory system where:
- Angiotensin II stimulates angiotensinogen release
- Renin (or des-angiotensin I-angiotensinogen) inhibits angiotensinogen release
- Angiotensin I has no direct effect on angiotensinogen release 3
Clinical and Physiological Significance
This feedback regulation has important implications for understanding RAAS dynamics:
During pregnancy, estrogen stimulates hepatic production of angiotensinogen, contributing to RAAS activation 4
Increased angiotensinogen production and plasma renin activity lead to increased angiotensin I concentrations, favoring augmented angiotensin II production 4
The feedback loop where angiotensin II upregulates angiotensinogen creates a self-amplifying system that can contribute to pathological states like hypertension 4
Intracellular angiotensin II regulates the expression of angiotensinogen and renin, generating an additional feedback loop 5
Clinical Implications
Understanding this regulatory mechanism has several clinical implications:
In hypertension management, blocking angiotensin II with ARBs not only prevents direct vasoconstriction but may also reduce angiotensinogen production 2
The estrogen-mediated increase in angiotensinogen production explains the association between oral contraceptive pills and hypertension 4
This feedback mechanism may contribute to treatment resistance in some hypertensive patients, as angiotensin II blockade could lead to compensatory increases in other components of the RAAS
Caveats and Considerations
The regulation of angiotensinogen by angiotensin II occurs alongside other regulatory mechanisms, including glucocorticoid effects 1
While angiotensin II upregulates angiotensinogen, it appears to downregulate ACE mRNA levels and activity in major sites of ACE synthesis (lung and testis) 6
The intracellular RAAS may operate somewhat independently from the circulatory system, with different enzymes catalyzing angiotensin II formation (chymase rather than ACE) 5
This positive feedback mechanism where angiotensin II upregulates angiotensinogen production represents an important regulatory aspect of the RAAS that contributes to both normal physiological function and potentially to pathological states like hypertension.