How does the Renin-Angiotensin-Aldosterone System (RAAS) work?

How the Renin-Angiotensin-Aldosterone System (RAAS) Works

The Renin-Angiotensin-Aldosterone System (RAAS) is a complex hormonal cascade that regulates blood pressure, fluid balance, and electrolyte homeostasis through two counterbalancing pathways: the classical ACE/Angiotensin II/AT1R pathway (promoting vasoconstriction and sodium retention) and the counter-regulatory ACE2/Angiotensin-(1-7)/Mas receptor pathway (promoting vasodilation and anti-remodeling effects). 1

Core RAAS Cascade

The RAAS operates through the following sequence:

1. Initiation:

   • Renin is secreted by the kidney's juxtaglomerular cells in response to:
     • Decreased blood volume
     • Decreased renal perfusion
     • Decreased sodium delivery to the distal tubule

2. Angiotensin Formation:

   • Renin cleaves angiotensinogen (produced by the liver) to form angiotensin I
   • Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II
   • Non-ACE pathways can also generate angiotensin II 2

3. Angiotensin II Actions:

   • Potent vasoconstriction
   • Stimulation of catecholamine release from adrenal medulla
   • Promotion of aldosterone secretion from adrenal cortex
   • Enhancement of sodium reabsorption
   • Inhibition of renin release (negative feedback loop) 2

4. Aldosterone Effects:

   • Increases sodium reabsorption in distal tubule and collecting duct
   • Promotes potassium excretion
   • Expands blood volume 1

Dual Pathway System

The RAAS functions through two opposing arms:

Classical Pathway (Vasoconstrictive)

• ACE → Angiotensin II → AT1 receptor activation
• Effects: vasoconstriction, sodium retention, inflammation, fibrosis

Counter-regulatory Pathway (Vasodilatory)

• ACE2 → Angiotensin-(1-7) → Mas receptor activation
• Effects: vasodilation, anti-inflammatory, anti-fibrotic 1

Physiological Regulation

The RAAS maintains homeostasis through:

• Blood Pressure Regulation: Angiotensin II increases blood pressure through direct vasoconstriction and indirect effects via aldosterone-mediated sodium retention
• Electrolyte Balance: Aldosterone regulates sodium retention and potassium excretion
• Fluid Status: The system responds to volume depletion by increasing sodium and water retention 1

Negative Feedback Mechanisms

• Angiotensin II inhibits renin release, creating a negative feedback loop
• When this loop is interrupted (as with ACE inhibitors or ARBs), compensatory increases in plasma renin concentration occur
• Direct renin inhibitors block this feedback effect, reducing PRA, angiotensin I, and angiotensin II 2

Clinical Significance

RAAS dysregulation contributes to:

• Hypertension
• Heart failure
• Chronic kidney disease
• Atherosclerosis
• End-organ damage 1, 3

Pharmacological Targets

Multiple points in the RAAS cascade serve as therapeutic targets:

• Renin inhibitors (e.g., aliskiren): Block the initial step of the cascade
• ACE inhibitors: Prevent conversion of angiotensin I to angiotensin II
• Angiotensin receptor blockers: Block AT1 receptor activation
• Mineralocorticoid receptor antagonists: Block aldosterone effects 1, 2

Important Considerations

• RAAS inhibition is contraindicated during pregnancy due to its critical developmental role 1
• The system has important tissue-specific effects beyond systemic circulation
• RAAS components can be produced locally in various tissues (brain, heart, blood vessels)
• Excessive RAAS activation promotes inflammation, oxidative stress, and pathological remodeling 1

The intricate balance of the RAAS is essential for cardiovascular and renal health, with dysregulation contributing to numerous pathological conditions.