Introduction
The renin–angiotensin–aldosterone system (RAAS) functions as a primary regulator of blood volume, electrolyte homeostasis, and systemic vascular resistance. Short-term decreases in arterial pressure elicit responses via the baroreceptor reflex, whereas the RAAS mediates both acute and chronic adjustments. Classical RAAS comprises 3 principal components: renin, angiotensin II, and aldosterone.[1][2] These components increase arterial pressure in response to reduced renal perfusion, decreased salt delivery to the distal convoluted tubule, and β-adrenergic stimulation. Recent research has expanded the understanding of RAAS through the identification of additional system components over the past decades. The present activity focuses exclusively on the classical pathway of RAAS (see Image. Renin–Angiotensin–Aldosterone System Classical Pathway).
Organ Systems Involved
The RAAS is ubiquitous and involves multiple organ systems. Major sites of activity include the kidneys, lungs, systemic vasculature, adrenal cortex, and brain.[3]
Function
The RAAS serves as a key mediator of cardiac, vascular, and renal physiology by regulating vascular tone and maintaining salt and water homeostasis. Beyond these physiological roles, the RAAS contributes significantly to the pathophysiology of hypertension, heart failure, other cardiovascular disorders, and renal diseases.[4][5] Pharmacological inhibition of RAAS overactivation improves outcomes in multiple cardiovascular and renal conditions.
Mechanism
Renin
Juxtaglomerular cells, located within the afferent arterioles of the kidney, contain prorenin. Activation of juxtaglomerular cells triggers the cleavage of prorenin to renin. Prorenin undergoes activation within the kidney via proteolytic cleavage, by enzymes such as proconvertase 1 and cathepsin B, or nonproteolytic conformational changes.[6][7][8]
Mature renin is stored in the granules of juxtaglomerular cells and released into the circulation in response to 4 principal stimuli. First, changes in renal perfusion are detected by the pressure transducer mechanism within afferent arterioles, which sense stretch via arteriolar mechanoreceptors. Second, sodium and chloride delivery to the distal convoluted tubule is monitored by the macula densa. Third, increased β-adrenergic sympathetic activity, acting through β1-receptors, promotes renin release, particularly during upright posture. Fourth, humoral factors regulate renin secretion. Angiotensin II provides short-loop negative feedback (see Angiotensin II). Potassium inversely influences renin release, with hypokalemia stimulating secretion and hyperkalemia causing suppression. Atrial natriuretic peptide inhibits renin secretion.[9][10][11]
Consequently, conditions that reduce renal perfusion or tubular sodium content stimulate renin release into the bloodstream. Circulating renin exhibits a half-life of 10 to 15 minutes.[12] Renin functions as the rate-limiting enzyme of the RAAS.[13]
Angiotensinogen
Angiotensinogen is primarily synthesized and constitutively secreted by the liver. Renin cleaves the N-terminal of angiotensinogen, generating angiotensin I.
Angiotensin I
Angiotensin I is a peptide with no known biological activity. The physiological role of this molecule is limited to serving as a precursor for angiotensin II.[14]
Angiotensin-Converting Enzyme
Angiotensin-converting enzyme (ACE) is expressed on the plasma membranes of vascular endothelial cells, predominantly within the pulmonary circulation.[15] ACE cleaves 2 amino acids from the C-terminus of angiotensin I, generating the biologically active peptide angiotensin II.
Angiotensin II
ACE generates angiotensin II by cleaving 2 amino acids from the C-terminus of angiotensin I. Angiotensin II serves as the principal mediator of RAAS physiological effects, including regulation of blood pressure, blood volume, and aldosterone secretion.[16] Circulating angiotensin II has a very short half-life of less than 60 seconds.[17] Peptidases degrade angiotensin II into angiotensin III and angiotensin IV. Angiotensin III retains full aldosterone-stimulating activity but mediates approximately 40% of the pressor effects of angiotensin II. Angiotensin IV exhibits minimal hemodynamic activity and primarily modulates neurotransmitter function.[18]
Angiotensin II exerts physiological effects on extracellular volume and blood pressure through 5 principal mechanisms. First, angiotensin II induces vasoconstriction by contracting vascular smooth muscle in arterioles.[19] Second, the peptide stimulates aldosterone secretion from the adrenal cortex in the zona glomerulosa by promoting transcription of CYP11B2 (aldosterone synthase).[20][21] Third, angiotensin II increases sodium reabsorption by enhancing the activity of the sodium-hydrogen antiporter in the proximal convoluted tubule.[22] Fourth, angiotensin II elevates sympathetic outflow from the central nervous system.[23] Fifth, the peptide triggers the release of vasopressin from the hypothalamus.[24]
Beyond these physiological roles, angiotensin II contributes to numerous pathophysiological processes, including oxidative stress, vascular smooth muscle contraction, endothelial dysfunction, fibrosis, and hypertrophic, anti-apoptotic, and promitogenic effects.[25][26][27] Through these mechanisms, angiotensin II participates in the development of hypertension, atherosclerotic disease, heart failure, and kidney disease.[28][29][30][31] The effects of angiotensin II are mediated by 2 receptor subtypes, type 1 and type 2, which elicit distinct and often opposing physiological responses.[32][33]
Angiotensin II t
ype 1 receptor
The angiotensin II type 1 receptor (AT1-R) is a G-protein-coupled receptor.[34] This receptor is widely expressed in multiple cell types, including the heart, vasculature, kidneys, adrenal glands, pituitary, and central nervous system.[35][36][37][38] Angiotensin II mediates vasoconstriction and sodium and water reabsorption through AT1-R activation.[39] Pathological activation of AT1-R promotes inflammation, fibrosis, oxidative stress, tissue remodeling, and elevated blood pressure.[40] Dysregulation of AT1-R is central to the pathophysiology of cardiac and renal diseases.[41][42]
Angiotensin II type 2 receptor
The angiotensin II type 2 receptor (AT2-R) is a G-protein-coupled receptor predominantly expressed in fetal tissues, with expression declining in adulthood.[43] In adult tissues, AT2-R is present in the heart, kidneys, adrenal glands, and brain.[44][45][46] AT2-R mediates effects opposing those of AT1-R, providing protective actions that inhibit inflammation, fibrosis, and central sympathetic outflow while promoting vasodilation.[47][48] Activation of AT2-R by angiotensin II induces vasodilation and natriuresis, counteracting the vasoconstriction and anti-natriuretic effects mediated by AT1-R.[49][50]
Aldosterone
Aldosterone is synthesized primarily in the zona glomerulosa of the adrenal cortex. Synthesis and secretion of aldosterone are primarily regulated by angiotensin II, adrenocorticotropic hormone, and extracellular potassium concentration.[51][52] The effects of aldosterone are mediated through nuclear cytosolic receptors.[53] Circulating aldosterone has a plasma half-life of less than 20 minutes.[54]
Aldosterone regulates electrolyte and renal homeostasis by binding to mineralocorticoid receptors on principal epithelial cells in the renal cortical collecting duct. Sodium reabsorption occurs via epithelial sodium channels (ENaC) on the apical membranes of principal cells. Aldosterone increases the abundance of ENaCs at the apical membrane, enhancing sodium reabsorption.[55] Activation of sodium–potassium adenosine triphosphatase (Na-K ATPase) at the basolateral membrane of principal cells also occurs, facilitating sodium transport into the extracellular space and increasing potassium uptake at the apical membrane.[56]
Aldosterone contributes to salt and water homeostasis by modulating thirst. The hormone also regulates salt appetite through mineralocorticoid receptors located in multiple regions of the brain.[57][58][59][60]
Clinical Significance
Overactivation of the RAAS has been implicated in the pathogenesis of multiple cardiovascular and renal diseases.[61][62][63] RAAS dysregulation also contributes to the development of primary hypertension.[64][65] Evidence for this relationship is supported by the efficacy of medications that block the RAAS at various steps.
Excess RAAS activity is implicated in secondary hypertension caused by primary hyperaldosteronism. Primary hyperaldosteronism results from autonomous aldosterone production by either an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia. Affected individuals typically present with suppressed renin, elevated aldosterone levels, and, often, hypokalemia.[66]
Primary hyperaldosteronism remains an underrecognized condition associated with increased cardiovascular and renal morbidity and mortality.[67] Screening for this condition is recommended in all patients with resistant hypertension. Early detection and timely management improve clinical outcomes.
Various medications target the RAAS at multiple points in the pathway. These agents reduce vasoconstriction and improve renal perfusion.[68] Blockade of RAAS components decreases inflammation, hypertrophy, and fibrosis.[69][70] Consequently, tissue remodeling in cardiac and renal structures is attenuated. Pharmacologic agents acting on the RAAS are summarized below.
Direct Renin Inhibitor
Aliskiren has not demonstrated improvement in renal or cardiovascular outcomes in patients with type 2 diabetes.[71][72] Clinical use of these agents remains limited due to the lack of benefit observed in trials.
Angiotensin-Converting Enzyme Inhibitors
Commonly used ACE inhibitors (ACEIs) include lisinopril, captopril, ramipril, enalapril, fosinopril, and benazepril. These drugs serve as 1st-line therapy for hypertension. ACEI therapy leads to improved cardiovascular outcomes, including reduced hospitalizations for heart failure and decreased cardiovascular mortality.[73][74] These agents also confer renoprotective effects, such as reducing microalbuminuria and slowing the progression of kidney disease, particularly in patients with type 2 diabetes.[75][76][77] Cough is a frequent adverse effect, resulting from inhibition of bradykinin breakdown, which can also rarely cause angioedema.
Angiotensin Receptor Blockers
Commonly used angiotensin receptor blockers (ARBs) include valsartan, candesartan, irbesartan, olmesartan, and telmisartan. These agents also serve as 1st-line therapy for hypertension. ARBs result in improved cardiovascular outcomes, including reductions in heart failure and cardiovascular mortality hospitalizations.[78][79][80] Renal benefits include reduced microalbuminuria and slower progression of kidney disease, including in patients with type 2 diabetes.[81][82][83] Unlike ACEIs, ARBs do not affect bradykinin metabolism, which mitigates the risk of cough.
Mineralocorticoid Receptor Antagonists
Spironolactone, eplerenone, and finerenone improve outcomes in patients with a history of heart failure by inhibiting myocardial fibrosis. Spironolactone and eplerenone reduce hospitalizations and mortality in patients with heart failure with both preserved and reduced ejection fraction.[84][85] Finerenone decreases hospitalizations due to heart failure and improves renal outcomes in patients with diabetic kidney disease.[86][87] These medications serve as 1st-line therapy for medically managed cases of primary hyperaldosteronism.
Aldosterone Synthase Blocker
Baxdrostat, a selective aldosterone synthase inhibitor, demonstrates promising results in patients with resistant hypertension, producing dose-dependent reductions in blood pressure in a recent phase 2 clinical trial. The mechanism of action involves inhibition of CYP11B2, thereby blocking aldosterone synthesis in the zona glomerulosa.[88]
Epithelial Sodium Channel Blockers
Amiloride and triamterene inhibit ENaCs without affecting mineralocorticoid receptors. These agents exert mild diuretic effects and may be combined with other diuretics to reduce potassium loss resulting from enhanced renal excretion (kaliuresis).
