The Renin-Angiotensin-Aldosterone System (RAAS)
The RAAS is a hormonal cascade that regulates blood pressure and fluid-electrolyte balance through a negative feedback loop involving renin, angiotensin II, and aldosterone, with downstream effects on renal sodium and water reabsorption, systemic arteriolar vasoconstriction, and sympathetic nervous system activation. 1
Primary Physiological Functions
Blood Pressure Regulation
- The RAAS cascade initiates in response to three triggers: decreases in blood pressure, reductions in sodium chloride delivery to the macula densa of the distal convoluted tubule, and stimulation of renal sympathetic nerves 1
- Renin is secreted by the kidneys and cleaves hepatic angiotensinogen to form angiotensin I 2
- Angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II, the primary active product 1, 2
Angiotensin II Actions
Angiotensin II elevates blood pressure through multiple mechanisms:
- Increases sodium reabsorption in the proximal convoluted tubule 1
- Promotes systemic arteriolar vasoconstriction 1
- Activates the sympathetic nervous system 1
- Increases thirst 1
- Stimulates aldosterone release from the adrenal cortex 1
- Stimulates antidiuretic hormone release from the pituitary 1
- Promotes catecholamine release from the adrenal medulla and prejunctional nerve endings 2
Aldosterone and Fluid Balance
- Aldosterone directly stimulates renal sodium and fluid retention to increase blood volume 1
- This completes the negative feedback loop, as angiotensin II also inhibits renin release 2
Broader Physiological Roles
Tissue-Level Functions
- RAAS functions as both a circulating hormone system and a local tissue hormone system (acting as a local mediator, neurotransmitter, or neuromodulator in the CNS) 3
- Every organ is affected by RAAS activation, influencing cell proliferation, inflammation, and fibrosis 4
Pregnancy-Specific Functions
- RAAS is crucial for cardiovascular and kidney development in the fetus 1
- Circulating and local tissue angiotensin II plays key roles in placentation, including trophoblast invasion and migration, as well as spiral artery remodeling 1
- ACE is concentrated in fetal endothelial cells throughout pregnancy, favoring enhanced angiotensin II production in placental vessels to support angiogenesis and fetal perfusion 1, 5
Clinical Significance
Pathophysiological Role
- Dysregulation of RAAS plays an important role in the pathogenesis of hypertension, cardiovascular disease, renal disorders, and atherosclerosis 3, 6, 7
- RAAS should be constantly suppressed, and any degree of excessive activity may lead to hypertension and associated target organ damage 8
Therapeutic Targeting
- RAAS is an important target for five distinctive classes of antihypertensive drugs: beta blockers, renin inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs), and aldosterone inhibitors 8
- Pharmacological interruption of RAAS has proven beneficial in treating hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy 3
Compensatory Mechanisms
Feedback Loop Dynamics
- All agents that inhibit RAAS suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration 2
- With ACE inhibitors and ARBs, this results in increased plasma renin activity 2
- With direct renin inhibitors like aliskiren, the effect of increased renin levels is blocked, so plasma renin activity, angiotensin I, and angiotensin II are all reduced 2