Aldosterone

Aldosterone is the principal mineralocorticoid hormone produced by the adrenal cortex. It is synthesized primarily by cells of the zona glomerulosa, the outermost layer of the adrenal cortex. Aldosterone plays a central role in maintaining extracellular fluid volume, electrolyte balance, and arterial blood pressure by regulating the renal handling of sodium, potassium, and hydrogen ions.

The major physiological targets of aldosterone are epithelial cells in the late distal tubule and collecting duct of the kidney. Aldosterone promotes sodium reabsorption while increasing potassium secretion. Because water tends to follow retained sodium when appropriate water-regulating mechanisms permit, aldosterone contributes indirectly to maintenance of extracellular fluid volume and blood pressure.

Aldosterone secretion is regulated predominantly by the renin-angiotensin-aldosterone system (RAAS) and the plasma potassium concentration. Angiotensin II and increased extracellular potassium strongly stimulate aldosterone production. Adrenocorticotropic hormone (ACTH) can also influence aldosterone secretion, but its role in long-term regulation is comparatively limited.

Site of Production

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex.

The zona glomerulosa lies immediately beneath the adrenal capsule and forms the outermost of the three major cortical zones.

Adrenal Cortical Zones

Zone	Major Hormonal Product
Zona glomerulosa	Mineralocorticoids, especially aldosterone
Zona fasciculata	Glucocorticoids, especially cortisol
Zona reticularis	Adrenal androgens, especially DHEA and DHEAS

Zona Glomerulosa

The zona glomerulosa consists of steroid-secreting cells arranged in rounded or arched clusters beneath the connective tissue capsule of the adrenal gland.

These cells possess the enzymatic machinery required for mineralocorticoid synthesis and are particularly responsive to angiotensin II and extracellular potassium.

Aldosterone as a Steroid Hormone

Aldosterone is a steroid hormone derived from cholesterol.

Because steroid hormones are lipid soluble, aldosterone can cross cell membranes and bind to intracellular receptors in target cells.

Mineralocorticoids

Mineralocorticoids are adrenal cortical steroids that influence electrolyte and water balance.

Aldosterone is the most important naturally occurring mineralocorticoid in humans.

Synthesis of Aldosterone

Aldosterone synthesis begins with cholesterol, the common precursor for all adrenal cortical steroid hormones.

A simplified pathway is:

Cholesterol → Pregnenolone → Progesterone → 11-Deoxycorticosterone → Corticosterone → Aldosterone

Cholesterol

Adrenal cortical cells obtain cholesterol from circulating lipoproteins, intracellular cholesterol stores, and endogenous synthesis.

Cholesterol must be transported into mitochondria before steroidogenesis can begin.

StAR Protein

The steroidogenic acute regulatory protein (StAR) facilitates transport of cholesterol toward the inner mitochondrial membrane.

This represents an important regulated step in adrenal steroid hormone synthesis.

Pregnenolone

Within mitochondria, cholesterol is converted into pregnenolone by the cholesterol side-chain cleavage enzyme.

Pregnenolone then enters pathways leading to different adrenal cortical hormones depending on the enzymes expressed by the cell.

Aldosterone Synthase

The terminal steps of aldosterone synthesis depend on aldosterone synthase, encoded by the CYP11B2 gene.

Aldosterone synthase is characteristically expressed in the zona glomerulosa and enables conversion of corticosterone through intermediate steps to aldosterone.

CYP11B2

CYP11B2 encodes a mitochondrial cytochrome P450 enzyme with activities required for the final stages of aldosterone biosynthesis.

Its restricted expression is an important reason the zona glomerulosa is specialized for aldosterone production.

Absence of CYP17A1

Zona glomerulosa cells lack significant CYP17A1 activity.

Consequently, these cells cannot efficiently produce cortisol or adrenal androgens and instead direct steroid precursors toward mineralocorticoid synthesis.

Aldosterone Synthesis Pathway

Stage	Major Product
Initial substrate	Cholesterol
First steroid	Pregnenolone
Intermediate	Progesterone
Mineralocorticoid precursor	11-Deoxycorticosterone
Intermediate	Corticosterone
Final major product	Aldosterone

Regulation of Aldosterone Secretion

Aldosterone secretion is controlled primarily by factors related to extracellular fluid volume and potassium homeostasis.

The two most important physiological stimuli are:

• Angiotensin II
• Increased extracellular potassium concentration

Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system is a coordinated hormonal pathway that helps maintain arterial pressure, extracellular fluid volume, and sodium balance.

Activation of this system ultimately increases angiotensin II formation and stimulates aldosterone secretion.

Renin

Renin is a proteolytic enzyme released by juxtaglomerular cells of the kidney.

Renin secretion increases in response to physiological signals indicating reduced effective renal perfusion or reduced sodium chloride delivery to the distal nephron.

Juxtaglomerular Cells

Juxtaglomerular cells are modified smooth muscle cells located mainly in the wall of the afferent arteriole near the vascular pole of the renal corpuscle.

These cells synthesize, store, and release renin.

Stimuli for Renin Release

Important stimuli for renin secretion include:

• Reduced renal perfusion pressure
• Reduced sodium chloride delivery to the macula densa
• Increased renal sympathetic activity through β1-adrenergic receptors

Angiotensinogen

Angiotensinogen is a circulating protein synthesized predominantly by the liver.

Renin cleaves angiotensinogen to form angiotensin I.

Angiotensin I

Angiotensin I has relatively limited direct biological activity but serves as the precursor of angiotensin II.

Angiotensin-Converting Enzyme

Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II.

ACE is expressed on endothelial surfaces in several tissues and is particularly associated physiologically with the pulmonary and systemic vascular endothelium.

Angiotensin II

Angiotensin II is a potent regulator of cardiovascular and renal physiology.

One of its important endocrine actions is direct stimulation of aldosterone secretion from zona glomerulosa cells.

RAAS Pathway

A simplified sequence of the RAAS is:

Reduced effective renal perfusion → Renin release → Angiotensinogen converted to angiotensin I → Angiotensin II formation → Aldosterone secretion → Increased renal sodium retention

Angiotensin II and Zona Glomerulosa

Angiotensin II binds primarily to AT1 receptors on zona glomerulosa cells.

Receptor activation increases intracellular signaling that promotes steroidogenesis and aldosterone synthesis.

Potassium Regulation

The extracellular potassium concentration directly regulates aldosterone secretion.

An increase in plasma potassium stimulates zona glomerulosa cells and increases aldosterone production.

Hyperkalemia

Elevated extracellular potassium depolarizes zona glomerulosa cell membranes and promotes calcium entry.

The resulting increase in intracellular calcium stimulates aldosterone synthesis and secretion.

Aldosterone Response to Hyperkalemia

Increased aldosterone enhances potassium secretion by the distal nephron.

This negative feedback mechanism helps return extracellular potassium toward its normal range.

Hypokalemia

Low extracellular potassium reduces the direct stimulation of zona glomerulosa cells and generally suppresses aldosterone secretion.

ACTH

Adrenocorticotropic hormone (ACTH) can acutely stimulate aldosterone secretion, but it is not the principal regulator of long-term aldosterone production.

The renin-angiotensin system and extracellular potassium are considerably more important for sustained physiological control.

Atrial Natriuretic Peptide

Atrial natriuretic peptide (ANP) is released primarily by atrial cardiomyocytes in response to increased atrial stretch.

ANP promotes sodium excretion and opposes several actions of the RAAS, including suppression of aldosterone secretion.

Major Regulators of Aldosterone

Factor	Effect on Aldosterone
Angiotensin II	Strong stimulation
Increased plasma potassium	Strong stimulation
ACTH	Acute or minor physiological stimulation
ANP	Inhibition
Reduced plasma potassium	Reduced stimulation

Target Organs

The kidney is the principal physiological target of aldosterone.

Aldosterone also acts on epithelial tissues outside the kidney, including portions of the colon and the ducts of sweat and salivary glands.

Renal Target Sites

Within the kidney, aldosterone acts predominantly on cells in the:

• Late distal convoluted tubule
• Connecting tubule
• Cortical collecting duct

Principal Cells

Principal cells of the distal nephron are major targets for aldosterone.

Aldosterone increases sodium reabsorption and potassium secretion by modifying the expression and activity of specific ion channels and transport proteins.

Mineralocorticoid Receptor

Aldosterone acts primarily through the intracellular mineralocorticoid receptor (MR).

After entering a target cell, aldosterone binds to the receptor, and the hormone-receptor complex regulates transcription of genes involved in electrolyte transport.

Epithelial Sodium Channel

Aldosterone increases the activity and abundance of the epithelial sodium channel (ENaC) in the apical membrane of principal cells.

ENaC allows sodium to move from tubular fluid into the epithelial cell.

Na+/K+-ATPase

Aldosterone promotes activity of the basolateral Na+/K+-ATPase.

This transporter moves sodium from the epithelial cell into the interstitial fluid while moving potassium into the cell.

Renal Outer Medullary Potassium Channel

Potassium entering principal cells through the Na+/K+-ATPase can be secreted into the tubular lumen through potassium channels, including the renal outer medullary potassium channel (ROMK).

Aldosterone therefore facilitates the coordinated reabsorption of sodium and secretion of potassium.

Principal Cell Effects

Transport Component	Effect of Aldosterone
ENaC	Increases sodium entry from tubular lumen
Na+/K+-ATPase	Increases basolateral sodium extrusion and potassium uptake
Potassium channels	Supports increased potassium secretion

Sodium Reabsorption

A major action of aldosterone is increased sodium reabsorption from tubular fluid into the extracellular compartment.

This conserves sodium that would otherwise be lost in the urine.

Water Retention

Aldosterone does not primarily act as a direct water-channel-regulating hormone.

However, retention of sodium contributes to retention of extracellular fluid when water is available and water balance is appropriately regulated by mechanisms including thirst and antidiuretic hormone.

Potassium Secretion

Aldosterone promotes potassium secretion into the distal nephron.

This action is particularly important in maintaining normal extracellular potassium concentration after increases in dietary potassium intake.

Hydrogen Ion Secretion

Aldosterone also contributes to acid-base regulation by promoting hydrogen ion secretion, particularly through α-intercalated cells of the collecting duct.

Intercalated Cells

Intercalated cells are specialized epithelial cells within the collecting duct involved in acid-base regulation.

Aldosterone can enhance mechanisms responsible for hydrogen ion secretion by α-intercalated cells.

Effect on Acid-Base Balance

Excessive aldosterone activity can increase renal hydrogen ion loss and contribute to metabolic alkalosis.

Conversely, inadequate mineralocorticoid activity can impair distal hydrogen ion secretion and contribute to metabolic acidosis.

Overall Renal Effects

Substance	Effect of Aldosterone
Sodium	Increased reabsorption
Potassium	Increased secretion
Hydrogen ions	Increased secretion
Water	Indirect retention associated with sodium conservation

Extracellular Fluid Volume

By increasing renal sodium conservation, aldosterone contributes to maintenance of extracellular fluid volume.

Changes in extracellular volume influence venous return, cardiac output, and arterial pressure.

Blood Pressure

Aldosterone contributes to long-term blood pressure regulation through its effects on renal sodium balance and extracellular fluid volume.

Excessive aldosterone activity can contribute to hypertension, whereas severe mineralocorticoid deficiency can contribute to volume depletion and hypotension.

Aldosterone Escape

Persistent aldosterone excess does not normally cause unlimited sodium and water retention.

As extracellular volume expands and arterial pressure rises, compensatory renal and hormonal mechanisms increase sodium excretion despite continued aldosterone activity. This phenomenon is known as aldosterone escape.

Pressure Natriuresis

Increased arterial pressure promotes renal sodium excretion through pressure natriuresis.

This mechanism contributes to limiting progressive extracellular volume expansion during chronic mineralocorticoid excess.

Aldosterone and the Colon

Aldosterone can increase sodium absorption and potassium secretion in the colon.

These effects become particularly relevant when aldosterone concentrations are elevated or renal electrolyte conservation is required.

Sweat Glands

Aldosterone promotes sodium conservation in the ducts of sweat glands.

This reduces sodium loss in sweat, particularly during physiological states in which mineralocorticoid activity is increased.

Salivary Glands

Aldosterone also influences electrolyte transport in salivary ducts.

It promotes sodium reabsorption and affects potassium secretion, modifying the final ionic composition of saliva.

11β-Hydroxysteroid Dehydrogenase Type 2

The mineralocorticoid receptor can bind both aldosterone and cortisol. Because circulating cortisol concentrations are much higher than aldosterone concentrations, mineralocorticoid-sensitive epithelial cells require a mechanism that protects the receptor from inappropriate activation by cortisol.

The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts active cortisol into cortisone, which has substantially less activity at the mineralocorticoid receptor.

Mineralocorticoid Receptor Selectivity

Expression of 11β-HSD2 allows aldosterone-sensitive tissues to respond selectively to aldosterone despite exposure to much higher circulating concentrations of cortisol.

Primary Hyperaldosteronism

Primary hyperaldosteronism results from autonomous or relatively autonomous excessive aldosterone production by the adrenal cortex.

Because aldosterone secretion is occurring independently of the normal renin stimulus, renin activity is typically suppressed.

Causes of Primary Hyperaldosteronism

Important causes include:

• Bilateral adrenal aldosterone-producing disease
• Aldosterone-producing adrenal adenoma
• Less common familial and adrenal cortical disorders

Conn Syndrome

The term Conn syndrome is traditionally associated with primary aldosteronism, particularly aldosterone-producing adrenal adenoma.

Excessive aldosterone causes increased sodium retention together with increased potassium and hydrogen ion secretion.

Clinical Features of Primary Aldosteronism

Common physiological and laboratory consequences can include:

• Hypertension
• Suppressed renin
• Hypokalemia in some patients
• Increased renal potassium loss
• Metabolic alkalosis in more pronounced cases

Hypokalemia

Excess aldosterone can increase renal potassium secretion sufficiently to produce hypokalemia.

However, normal serum potassium does not exclude primary aldosteronism.

Metabolic Alkalosis

Enhanced distal hydrogen ion secretion can contribute to metabolic alkalosis in states of substantial mineralocorticoid excess.

Secondary Hyperaldosteronism

Secondary hyperaldosteronism occurs when aldosterone production increases appropriately in response to increased renin-angiotensin system activity.

In contrast with primary aldosteronism, renin is generally increased rather than suppressed.

Causes of Secondary Hyperaldosteronism

Secondary activation can occur in conditions associated with reduced effective arterial blood volume, reduced renal perfusion, or excessive renin production.

The underlying mechanism is activation of the RAAS rather than autonomous secretion by the adrenal cortex.

Primary Versus Secondary Hyperaldosteronism

Feature	Primary Hyperaldosteronism	Secondary Hyperaldosteronism
Aldosterone	Elevated	Elevated
Renin	Usually suppressed	Usually elevated
Primary abnormality	Adrenal aldosterone production	Activation of renin-angiotensin system
Mechanism	Relatively autonomous secretion	Physiological response to renin stimulation

Hypoaldosteronism

Hypoaldosteronism refers to inadequate aldosterone production or activity.

Reduced mineralocorticoid action decreases renal sodium conservation and impairs potassium and hydrogen ion excretion.

Consequences of Aldosterone Deficiency

Potential consequences include:

• Hyperkalemia
• Renal sodium loss
• Reduced extracellular fluid volume
• Hypotension
• Metabolic acidosis

Primary Adrenal Insufficiency

In primary adrenal insufficiency, destruction or dysfunction of the adrenal cortex can impair production of both cortisol and aldosterone.

Mineralocorticoid deficiency contributes to sodium loss, volume depletion, hyperkalemia, and hypotension.

Secondary Adrenal Insufficiency

In secondary adrenal insufficiency caused by inadequate ACTH stimulation, aldosterone production is generally much better preserved than cortisol production.

This occurs because aldosterone is regulated primarily by the renin-angiotensin system and extracellular potassium rather than ACTH.

Hyporeninemic Hypoaldosteronism

Reduced renin production can result in insufficient stimulation of aldosterone secretion.

This pattern can contribute to hyperkalemia and a form of normal-anion-gap metabolic acidosis associated with impaired distal potassium and hydrogen ion excretion.

Type IV Renal Tubular Acidosis

Type IV renal tubular acidosis is commonly associated with aldosterone deficiency or resistance to aldosterone action.

Hyperkalemia is a characteristic feature and distinguishes it from several other forms of renal tubular acidosis.

Apparent Mineralocorticoid Excess

Mineralocorticoid receptor activation can occur even when aldosterone itself is not elevated.

Impaired 11β-HSD2 activity allows cortisol to activate mineralocorticoid receptors more extensively, producing physiological effects resembling mineralocorticoid excess.

Aldosterone Resistance

Defects affecting mineralocorticoid receptor signaling or downstream sodium transport can produce resistance to aldosterone.

Despite elevated aldosterone concentrations, target tissues may fail to produce the expected sodium-retaining and potassium-excreting responses.

Pseudohypoaldosteronism

Pseudohypoaldosteronism refers to disorders in which aldosterone concentrations may be elevated but target tissues respond inadequately to mineralocorticoid signaling.

The resulting physiological pattern can include salt wasting, hyperkalemia, and metabolic acidosis.

Aldosterone-Renin Ratio

The aldosterone-renin ratio is commonly used as a screening approach when evaluating suspected primary aldosteronism.

The interpretation depends on the absolute aldosterone and renin values as well as medications, potassium status, sodium intake, posture, sampling conditions, and the specific laboratory methods used.

Adrenal Imaging

CT imaging can identify structural abnormalities of the adrenal glands in patients with confirmed biochemical evidence of primary aldosteronism.

However, structural imaging alone cannot always determine whether an adrenal lesion is responsible for excessive hormone production.

Adrenal Venous Sampling

Adrenal venous sampling can compare hormone secretion from the right and left adrenal glands.

It is used in selected patients with primary aldosteronism to determine whether excessive aldosterone production is unilateral or bilateral.

Aldosterone Antagonists

The physiological actions of aldosterone can be reduced by drugs that antagonize the mineralocorticoid receptor.

Mineralocorticoid receptor antagonism decreases sodium-retaining effects while reducing potassium secretion.

Spironolactone

Spironolactone is a mineralocorticoid receptor antagonist that blocks aldosterone action in target tissues.

Its effects include increased sodium excretion and reduced renal potassium loss.

Eplerenone

Eplerenone is another mineralocorticoid receptor antagonist with greater selectivity for the mineralocorticoid receptor than spironolactone.

ACE Inhibitors and Aldosterone

Inhibition of angiotensin-converting enzyme reduces formation of angiotensin II.

Reduced angiotensin II signaling can decrease aldosterone secretion and therefore reduce renal potassium excretion.

Angiotensin Receptor Blockade

Blocking angiotensin II receptors reduces the ability of angiotensin II to stimulate zona glomerulosa cells.

This can decrease aldosterone production as part of the broader suppression of RAAS activity.

Aldosterone and Potassium Homeostasis

The relationship between aldosterone and potassium forms an important feedback system.

Increasing extracellular potassium stimulates aldosterone, and aldosterone then increases renal potassium secretion.

Potassium Feedback Loop

A simplified feedback sequence is:

Increased plasma K+ → Increased aldosterone secretion → Increased distal nephron K+ secretion → Reduction of plasma K+

Aldosterone and Sodium Homeostasis

Aldosterone contributes to sodium homeostasis by adjusting sodium reabsorption in the distal nephron.

Although only a fraction of filtered sodium reaches aldosterone-sensitive nephron segments, regulation at these sites is important for fine control of total-body sodium balance.

Aldosterone and Volume Depletion

Volume depletion can activate renin secretion and increase angiotensin II formation.

The resulting increase in aldosterone helps conserve sodium and supports restoration of extracellular fluid volume.

Aldosterone and Volume Expansion

Expansion of extracellular fluid volume generally suppresses renin release and reduces activation of the RAAS.

This decreases aldosterone stimulation and facilitates renal sodium excretion.

Aldosterone Versus ADH

Aldosterone and antidiuretic hormone (ADH) both participate in fluid homeostasis but act through different mechanisms.

Feature	Aldosterone	ADH
Major source	Adrenal cortex	Released from posterior pituitary after hypothalamic synthesis
Major regulated substance	Sodium and potassium balance	Water balance
Important renal target	Distal nephron	Collecting duct
Major mechanism	Changes ion transport proteins	Promotes aquaporin-2 insertion

Aldosterone Versus Cortisol

Feature	Aldosterone	Cortisol
Primary cortical zone	Zona glomerulosa	Zona fasciculata
Hormone class	Mineralocorticoid	Glucocorticoid
Major regulation	Angiotensin II and potassium	ACTH
Major physiological role	Electrolyte and extracellular volume regulation	Metabolic and stress-related regulation

Aldosterone Versus ANP

Aldosterone and ANP have broadly opposing effects on sodium balance.

Aldosterone promotes sodium conservation, whereas ANP promotes renal sodium excretion and contributes to suppression of the renin-angiotensin-aldosterone system.

Key Features of Aldosterone

Feature	Key Point
Hormone type	Mineralocorticoid steroid hormone
Site of synthesis	Zona glomerulosa
Precursor	Cholesterol
Key terminal enzyme	Aldosterone synthase, CYP11B2
Major stimulators	Angiotensin II and increased potassium
Major renal targets	Late distal nephron and collecting duct
Sodium effect	Increased reabsorption
Potassium effect	Increased secretion
Hydrogen ion effect	Increased secretion
Receptor	Mineralocorticoid receptor
Major physiological role	Electrolyte, extracellular volume and blood pressure regulation

Clinical Associations

Condition	Typical Aldosterone Relationship
Primary aldosteronism	Excess aldosterone with suppressed renin
Secondary hyperaldosteronism	Increased aldosterone secondary to increased renin activity
Primary adrenal insufficiency	Reduced aldosterone production
Hyporeninemic hypoaldosteronism	Reduced renin and inadequate aldosterone
Pseudohypoaldosteronism	Reduced response to aldosterone despite elevated hormone levels

Anatomical and Physiological Importance

Aldosterone links the adrenal cortex closely with renal and cardiovascular physiology. Its production in the zona glomerulosa is regulated predominantly by angiotensin II and extracellular potassium, allowing adrenal hormone secretion to respond directly to changes in circulatory volume and electrolyte balance.

At the kidney, aldosterone acts mainly on the distal nephron to increase sodium reabsorption while promoting potassium and hydrogen ion secretion. These actions contribute to extracellular fluid volume, potassium homeostasis, acid-base balance, and long-term regulation of arterial pressure.

Abnormal aldosterone production or action therefore produces characteristic physiological disturbances. Excessive aldosterone can contribute to hypertension, potassium loss, and metabolic alkalosis, whereas deficient aldosterone activity can cause sodium wasting, volume depletion, hyperkalemia, and metabolic acidosis. The relationship between aldosterone, renin, potassium, and renal electrolyte transport is consequently central to understanding both normal endocrine physiology and disorders of the adrenal cortex.