Whole-Body Na ⁺ Balance

As described in Chapter 1 , steady-state balance describes the process by which the addition of substances to the body is matched by their equivalent loss from the body. Decades of research has established that the kidneys are the major route for the excretion of ingested Na ⁺ (primarily as NaCl). Normally, approximately 90% of ingested Na ⁺ is excreted in the urine, with the remaining 10% excreted in feces and in sweat. Although the amount of Na ⁺ lost from the body in sweat and feces can vary, it is not regulated to maintain steady-state whole-body Na ⁺ balance. In contrast the renal excretion of Na ⁺ is regulated so that steady-state balance is achieved.

The classical explanation for how whole-body Na ⁺ balance is maintained in the face of changing dietary NaCl intake is depicted in Fig. 6.2 , which for simplicity assumes 100% of ingested Na ⁺ is excreted in the urine. In response to an increase in dietary NaCl, the kidneys increase NaCl excretion. However, it takes several days before a new steady state is achieved. This results in a transient period of positive Na ⁺ balance (intake > excretion), with an increase in ECF volume (because of concomitant water retention to maintain ECF osmolality constant). This increase in ECF volume manifests itself as an increase in body weight (1 L = 1 kg). When dietary NaCl is reduced, a new steady state is again achieved after several days, with the intervening period of negative Na ⁺ balance (intake < excretion) causing ECF volume and body weight to decrease.

Response of the kidneys to an acute change in Na ⁺ ingestion. Na ⁺ excretion by the kidneys (dashed line) lags behind step changes in Na ⁺ intake (lower panel, solid line) . The change in extracellular fluid volume that occurs during the periods of positive and negative Na ⁺ balance is reflected in acute alterations in body weight.

It is important to note that the kidneys can vary the excretion of Na ⁺ over a very wide range of intake (10 to 1000 mEq/day) with only modest or no long-term change in ECF volume.

In the Clinic

Long-term balance studies under carefully controlled conditions suggest that with a transition from ingesting a low-salt diet to ingesting a high-salt diet, there is an increase in ECF volume, which manifests itself as an increase in body weight ( Fig. 6.3 ). However, after 2 weeks on the high-salt diet, ECF volume, body Na ⁺ content, and body weight return to their previous values. These changes are associated with a suppression of aldosterone levels. Additional studies are required to confirm these observations and to determine their clinical significance.

Changes in body weight, extracellular fluid (ECF) volume, total body Na ⁺ content, and aldosterone after change from a low-NaCl to a high-NaCl diet. See the text for details.

Adapted from Rakova N, Juttner K, Dahlman A, et al: Long-term space flight simulation reveals infradian rhythmicity in human Na ⁺ balance. Cell Metabol 17:125, 2013.

Concept of Effective Circulating Volume

As described in Chapter 1 , the ECF is subdivided into two compartments: blood plasma and interstitial fluid. Plasma volume is a determinant of vascular volume and thus blood pressure and cardiac output. The maintenance of Na ⁺ balance, and thus ECF volume, involves a complex system of sensors and effector signals that act primarily on the kidneys to regulate the excretion of NaCl. As can be appreciated from the dependence of vascular volume, blood pressure, and cardiac output on ECF volume, this complex system is designed to ensure adequate tissue perfusion. Because the primary sensors of this system are located in the large vessels of the vascular system, changes in vascular volume, blood pressure, and cardiac output are the principal factors regulating renal NaCl excretion (described later in this chapter).

In a healthy person, changes in ECF volume result in parallel changes in vascular volume, blood pressure, and cardiac output. Thus a decrease in ECF volume, a situation termed volume contraction , results in reduced vascular volume, blood pressure, and cardiac output. Conversely an increase in ECF volume, a situation termed volume expansion , results in increased vascular volume, blood pressure, and cardiac output. The degree to which these cardiovascular parameters change depends on the degree of volume contraction or expansion and the effectiveness of cardiovascular reflex mechanisms. When a person is volume contracted, renal NaCl excretion is reduced. Conversely with volume expansion, renal NaCl excretion is enhanced (i.e., natriuresis ).

However, in some pathologic conditions (e.g., congestive heart failure and hepatic cirrhosis), the renal excretion of NaCl is not reflective of the ECF volume. In both these situations the volume of the ECF is increased. However, instead of increased renal NaCl excretion, as would be expected, a reduction in the renal excretion of NaCl occurs. To explain renal Na ⁺ handling in these situations, it is necessary to understand the concept of effective circulating volume (ECV) . Unlike the ECF, the ECV is not a measurable and distinct body fluid compartment. The ECV is the portion of the ECF that is contained within the vascular system and is “effectively” perfusing the tissues ( effective arterial blood volume is another commonly used term). More specifically the ECV reflects the perfusion of those portions of the vascular system that contain the volume sensors (described later in this chapter).

In healthy persons, ECV varies directly with the volume of the ECF and in particular the volume of the vascular system (arterial and venous), arterial blood pressure, and cardiac output. However, as noted, this is not the case in certain pathologic conditions. In the remaining sections of this chapter, the relationship between ECF volume and renal NaCl excretion in healthy adults, where changes in ECV and ECF volume occur in parallel, is examined.

Volume-Sensing Systems

The ECF volume (or ECV) is monitored by multiple sensors ( Box 6.1 ). A number of the sensors are located in the vascular system, and they monitor its fullness and pressure. These receptors typically are called volume receptors; because they respond to pressure-induced stretch of the walls of the receptor (e.g., blood vessels or cardiac atria), they also are referred to as baroreceptors (see Chapter 5 ). Evidence exists for Na ⁺ sensors within the central nervous system (CNS), as well as in the gastrointestinal tract and liver. The extent to which these sensors contribute to regulating Na ⁺ balance and thus ECF volume is not well understood. Therefore they are not considered further, and only the role of the vascular receptors in monitoring ECF volume (or ECV) is described.

Renin-Angiotensin-Aldosterone System

Cells in the afferent arterioles ( juxtaglomerular cells ) are the site of synthesis, storage, and release of the proteolytic enzyme renin. Three factors are important in stimulating renin secretion:

• 1.
  

  Perfusion pressure. When perfusion pressure to the kidneys is reduced, renin secretion by the afferent arteriole is stimulated. Conversely, an increase in perfusion pressure inhibits renin release by the afferent arteriole.

  
  
  
  

  At the Cellular Level

  
  

  
  

  A new renal hormone has been discovered, a flavin adenine dinucleotide–dependent amine oxidase named renalase . Renalase is similar in structure to monoamine oxidase and breaks down catecholamines (e.g., epinephrine and norepinephrine). Several tissues (e.g., skeletal muscle, heart, and small intestine) express renalase, but the kidneys secrete the enzyme into the circulation. Because individuals with chronic renal failure have very low levels of renalase in their plasma, the kidney is likely the primary source of the circulating enzyme. In experimental animals, infusion of renalase decreases blood pressure and heart contractility. Although the precise role of renalase in cardiovascular function and blood pressure regulation is not known, it may be important in modulating the effects of the sympathetic nervous system and especially the effects of the sympathetic nerves on the kidney.

  
  
  
  
• 2.
  

  Sympathetic nerve activity. Activation of the sympathetic nerve fibers that innervate the afferent arterioles increases renin secretion via β-adrenergic receptor stimulation. Renin secretion is decreased as renal sympathetic nerve activity is decreased.

  
  
• 3.
  

  Delivery of NaCl to the macula densa. Delivery of NaCl to the macula densa regulates the GFR by a process termed tubuloglomerular feedback (see Chapter 3 ). In addition, the macula densa plays a role in renin secretion. When NaCl delivery to the macula densa is decreased, renin secretion is enhanced. Conversely, an increase in NaCl delivery inhibits renin secretion. It is likely that macula densa–mediated renin secretion helps maintain systemic arterial pressure under conditions of a reduced intravascular volume. For example, when intravascular volume is reduced, perfusion of body tissues (including the kidneys) decreases, which in turn decreases the GFR and the filtered amount of NaCl. The reduced delivery of NaCl to the macula densa stimulates renin secretion, which then generates angiotensin II (a potent vasoconstrictor) to increase the blood pressure and thereby maintain tissue perfusion.

At the Cellular Level

Although many tissues express renin (e.g., brain, heart, and adrenal gland tissues), the primary source of circulating renin is the kidneys. Renin is secreted by juxtaglomerular cells located in the afferent arteriole. At the cellular level, renin secretion is mediated by the fusion of renin-containing granules with the luminal membrane of the cell. This process is stimulated by a decrease in intracellular [Ca ⁺⁺ ], a response opposite to that of most secretory cells where secretion is normally stimulated by an increase in intracellular [Ca ⁺⁺ ]. Thus anything that increases intracellular [Ca ⁺⁺ ], including stretch of the afferent arteriole (myogenic control of renin secretion), angiotensin II (feedback inhibition), and endothelin, inhibits renin secretion. Renin release is also stimulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. Accordingly, anything that increases intracellular cAMP stimulates renin secretion, which includes norepinephrine acting through β-adrenergic receptors and prostaglandin E ₂ . Increases in intracellular cyclic guanosine monophosphate (cGMP) have been found to stimulate renin secretion in some situations and to inhibit secretion in others. Notably, two substances that increase intracellular cGMP are natriuretic peptides and nitric oxide. Nitric oxide stimulates renin secretion, whereas atrial natriuretic peptide and brain natriuretic peptide are inhibitory. The control of renin secretion by the macula densa (see Chapter 3 ) may involve paracrine factors such as prostaglandin E ₂ (which stimulates renin secretion when NaCl delivery to the macula densa is decreased) and adenosine (which inhibits renin secretion when NaCl delivery to the macular densa is increased).

Fig. 6.4 summarizes the essential components of the renin-angiotensin-aldosterone system . Renin alone does not have a physiologic function; it functions as a proteolytic enzyme. Its principal substrate is a circulating protein, angiotensinogen , which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10-amino-acid peptide, angiotensin I . Angiotensin I is further cleaved to an 8-amino-acid peptide, angiotensin II , by a converting enzyme ( angiotensin-converting enzyme [ACE] ) found on the surface of vascular endothelial cells. Pulmonary and renal endothelial cells are important sites for the bioconversion of angiotensin I to angiotensin II. ACE also degrades bradykinin, a potent vasodilator. Angiotensin II has several important physiologic functions, including the following:

• 1.
  

  Stimulation of aldosterone secretion by the adrenal cortex

  
  
• 2.
  

  Arteriolar vasoconstriction, which increases blood pressure

  
  
• 3.
  

  Stimulation of AVP secretion and thirst

  
  
• 4.
  

  Enhancement of NaCl reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, distal tubule, and collecting duct

Schematic representation of the essential components of the renin-angiotensin-aldosterone system. Activation of this system results in a decrease in the excretion of Na ⁺ and water by the kidneys. Note: Angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme, which is present on all vascular endothelial cells. As shown, the endothelial cells within the lungs play a significant role in this conversion process. AVP, Arginine vasopressin.

The effect on the proximal tubule is quantitatively the largest.

Angiotensin II is an important secretagogue for aldosterone . An increase in the plasma K ⁺ concentration is the other important stimulus for aldosterone secretion (see Chapter 7 ). Aldosterone is a steroid hormone produced by the glomerulosa cells of the adrenal cortex. Aldosterone acts in a number of ways on the kidneys (see Chapter 4 ). With regard to the regulation of the ECF volume, aldosterone reduces NaCl excretion by stimulating its reabsorption by several nephron segments. Most importantly it stimulates NaCl reabsorption in the aldosterone-sensitive distal nephron (ASDN) , which consists of the latter portion of the distal tubule and the collecting duct. To a lesser extent it also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop and the early portion of the distal tubule. ^a

Aldosterone has many cellular actions in the ASDN, including increasing the abundance and activity of ENaC in the apical membrane of principal cells and the abundance of Na ⁺ -K ⁺ –adenosine triphosphatase (ATPase) in the basolateral membrane of these same cells. As a result, Na ⁺ entry into the cell across the apical membrane is enhanced, as is its extrusion from the cell across the basolateral membrane. Thus net reabsorption of NaCl is increased (Cl ^– reabsorption is mostly passive and secondary to Na ⁺ reabsorption). Aldosterone also increases the abundance of the Na ⁺ -K ⁺ -2Cl ^– symporter in the thick ascending limb of Henle’s loop and the Na ⁺ -Cl ^– symporter in the early distal tubule (indirect effect), thereby stimulating NaCl reabsorption in these nephron segments.

Aldosterone selectivity and sensitivity are conferred by mineralocorticoid receptors present in cells in the ASDN, as well as by the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Because the mineralocorticoid receptor also binds glucocorticoids, 11β-HSD2 is required for aldosterone to specifically activate the mineralocorticoid receptor because it metabolizes glucocorticoids and thus prevents them from binding to the mineralocorticoid receptor.

In the Clinic

Diseases of the adrenal cortex can alter aldosterone levels and thereby impair the ability of the kidneys to maintain Na ⁺ balance and euvolemia. With decreased secretion of aldosterone ( hypoaldosteronism ), the reabsorption of Na ⁺ by the ASDN (late distal tubule and collecting duct) is reduced and NaCl is lost in the urine. Because urinary NaCl loss can exceed the amount of NaCl ingested in the diet, negative Na ⁺ balance ensues and the ECF volume decreases. These patients typically have decreased blood pressure. With increased aldosterone secretion ( hyperaldosteronism ), which can occur with an aldosterone secreting adrenal tumor, blood pressure is elevated. Interestingly, NaCl retention, as would be expected in the setting of high circulating aldosterone levels, does not occur. Instead the kidneys “escape” from the NaCl retaining action of aldosterone. This phenomenon, termed aldosterone or mineralocorticoid escape , is incompletely understood, but several mechanisms are likely involved. One mechanism is a pressure natriuresis caused by the elevated blood pressure. By this mechanism, hydrostatic pressure in the peritubular capillaries of the kidneys is elevated; this in turn inhibits proximal tubule reabsorption (see Chapter 4 ), leading to the natriuresis. It has also been found that aldosterone escape is associated with a decrease in abundance of the Na ⁺ -Cl ^– symporter in the early distal tubule. Finally, urinary adenosine triphosphate (ATP), which is elevated in this condition, inhibits the activity of the epithelial sodium channel (ENaC) in the ASDN.

As summarized in Box 6.2 , activation of the renin-angiotensin-aldosterone system, as occurs with ECF volume depletion, decreases the excretion of NaCl by the kidneys. Conversely, this system is suppressed by ECF volume expansion, thereby enhancing renal NaCl excretion.

Volume Sensors in the Low-Pressure Cardiopulmonary Circuit

Volume sensors (i.e., baroreceptors), which are located within the walls of the cardiac atria, right ventricle, and large pulmonary vessels, respond to distention of these structures. Because the low-pressure venous side of the circulatory system has a high compliance, these sensors respond mainly to the “fullness” of the vascular system. These baroreceptors send signals to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The activity of these sensors modulates both sympathetic nerve outflow and AVP secretion. For example, a decrease in filling of the pulmonary vessels and cardiac atria increases sympathetic nerve activity and stimulates AVP secretion. Conversely, distention of these structures decreases sympathetic nerve activity. In general, 5% to 10% changes in blood volume and pressure are necessary to evoke a response.

The cardiac atria possess an additional mechanism related to the control of renal NaCl excretion. The myocytes of the atria synthesize and store a peptide hormone. This hormone, termed atrial natriuretic peptide (ANP) , is released when the atria are distended, which, by mechanisms outlined later in this chapter, reduces blood pressure and increases the excretion of NaCl and water by the kidneys. The ventricles of the heart also produce a natriuretic peptide termed brain natriuretic peptide (BNP) , so named because it was first isolated from the brain. Like ANP, BNP is released from the ventricular myocytes by distention of the ventricles. Its actions are similar to those of ANP.

Volume Sensors in the High-Pressure Arterial Circuit

Baroreceptors also are present in the arterial side of the circulatory system; they are located in the wall of the aortic arch, carotid sinus, and afferent arterioles of the kidneys. The aortic arch and carotid baroreceptors send input to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The response to this input alters sympathetic outflow and AVP secretion. Thus a decrease in blood pressure increases sympathetic nerve activity and AVP secretion. An increase in pressure tends to reduce sympathetic nerve activity (and activate parasympathetic nerve activity). The sensitivity of the high-pressure baroreceptors is similar to that in the low-pressure side of the vascular system; 5% to 10% changes in pressure are needed to evoke a response.

The juxtaglomerular apparatus of the kidneys (see Chapter 2 ), particularly the afferent arteriole, responds directly to changes in pressure. If perfusion pressure in the afferent arteriole is reduced, renin is released from the myocytes. Renin secretion is suppressed when perfusion pressure is increased. As described later in this chapter, renin determines blood levels of angiotensin II and aldosterone, both of which play an important role in regulating renal NaCl excretion.

Of the two classes of baroreceptors, those on the high-pressure side of the vascular system appear to be more important in influencing sympathetic tone and AVP secretion. For example, patients with congestive heart failure often have an increased vascular volume with dilation of the atria and ventricles, which would be expected to decrease sympathetic tone and inhibit AVP secretion via the low-pressure baroreceptors. However, sympathetic tone often is increased and AVP secretion often is stimulated in these patients (the renin-angiotensin-aldosterone system also is activated). This phenomenon reflects the activation of baroreceptors in the high-pressure arterial circuit in response to reduced blood pressure and cardiac output secondary to the failing heart (i.e., the high-pressure baroreceptors detect a reduced ECV and misinterpret this signal as indicative of reduced ECF volume).

Volume Sensor Signals

When the vascular volume sensors have detected a change in ECV, which under normal conditions reflects ECF volume, they send signals to the kidneys, which result in appropriate adjustments in NaCl and water excretion. Accordingly, when the ECF volume is expanded, renal NaCl and water excretion are increased. Conversely, when the ECF volume is contracted, renal NaCl and water excretion are reduced. The signals involved in coupling the volume sensors to the kidneys are both neural and hormonal. These signals are summarized in Box 6.2 , as are their effects on renal NaCl and water excretion.

b The percentage of the filtered amount of Na+ excreted in the urine is termed fractional excretion (amount excreted/amount filtered). In this example, the fractional excretion of Na ⁺ is 140 mEq/day/25,200 mEq/day = 0.005, or 0.5%.

Renal Sympathetic Nerves

As described in Chapter 2 , sympathetic nerve fibers innervate the afferent and efferent arterioles of the glomerulus, as well as the nephron cells. With negative Na ⁺ balance (i.e., ECF volume contraction), baroreceptors in both the low- and high-pressure vascular circuits stimulate the sympathetic input to the kidneys. This stimulation has the following effects:

• 1.
  

  The afferent and efferent arterioles constrict in response to α-adrenergic stimulation. This vasoconstriction predominantly affects the afferent arteriole, effectively reducing hydrostatic pressure within the glomerular capillary lumen and decreasing glomerular filtration. The resulting reduction in the glomerular filtration rate (GFR) reduces the filtered amount of Na ⁺ to the nephrons.

  
  
• 2.
  

  Renin secretion is stimulated by the cells of the afferent arterioles in response to β-adrenergic receptor stimulation. As described later, renin ultimately increases the circulating levels of angiotensin II and aldosterone.

  
  
• 3.
  

  NaCl reabsorption along the nephron is directly stimulated by α-adrenergic stimulation, effectively reducing the fraction of filtered Na ⁺ that is ultimately excreted. Quantitatively the most important segment influenced by sympathetic nerve activity is the proximal tubule.

As a result of these combined actions, increased renal sympathetic nerve activity decreases net NaCl excretion, an adaptive response that works to restore ECF volume to normal, which is a state termed euvolemia . With positive Na ⁺ balance (i.e., ECF volume expansion), renal sympathetic nerve activity is reduced, which generally reverses the effects just described.

Renin-Angiotensin-Aldosterone System

Cells in the afferent arterioles ( juxtaglomerular cells ) are the site of synthesis, storage, and release of the proteolytic enzyme renin. Three factors are important in stimulating renin secretion:

• 1.
  

  Perfusion pressure. When perfusion pressure to the kidneys is reduced, renin secretion by the afferent arteriole is stimulated. Conversely, an increase in perfusion pressure inhibits renin release by the afferent arteriole.

  
  
  
  

  At the Cellular Level

  
  

  
  

  A new renal hormone has been discovered, a flavin adenine dinucleotide–dependent amine oxidase named renalase . Renalase is similar in structure to monoamine oxidase and breaks down catecholamines (e.g., epinephrine and norepinephrine). Several tissues (e.g., skeletal muscle, heart, and small intestine) express renalase, but the kidneys secrete the enzyme into the circulation. Because individuals with chronic renal failure have very low levels of renalase in their plasma, the kidney is likely the primary source of the circulating enzyme. In experimental animals, infusion of renalase decreases blood pressure and heart contractility. Although the precise role of renalase in cardiovascular function and blood pressure regulation is not known, it may be important in modulating the effects of the sympathetic nervous system and especially the effects of the sympathetic nerves on the kidney.

  
  
  
  
• 2.
  

  Sympathetic nerve activity. Activation of the sympathetic nerve fibers that innervate the afferent arterioles increases renin secretion via β-adrenergic receptor stimulation. Renin secretion is decreased as renal sympathetic nerve activity is decreased.

  
  
• 3.
  

  Delivery of NaCl to the macula densa. Delivery of NaCl to the macula densa regulates the GFR by a process termed tubuloglomerular feedback (see Chapter 3 ). In addition, the macula densa plays a role in renin secretion. When NaCl delivery to the macula densa is decreased, renin secretion is enhanced. Conversely, an increase in NaCl delivery inhibits renin secretion. It is likely that macula densa–mediated renin secretion helps maintain systemic arterial pressure under conditions of a reduced intravascular volume. For example, when intravascular volume is reduced, perfusion of body tissues (including the kidneys) decreases, which in turn decreases the GFR and the filtered amount of NaCl. The reduced delivery of NaCl to the macula densa stimulates renin secretion, which then generates angiotensin II (a potent vasoconstrictor) to increase the blood pressure and thereby maintain tissue perfusion.

At the Cellular Level

Although many tissues express renin (e.g., brain, heart, and adrenal gland tissues), the primary source of circulating renin is the kidneys. Renin is secreted by juxtaglomerular cells located in the afferent arteriole. At the cellular level, renin secretion is mediated by the fusion of renin-containing granules with the luminal membrane of the cell. This process is stimulated by a decrease in intracellular [Ca ⁺⁺ ], a response opposite to that of most secretory cells where secretion is normally stimulated by an increase in intracellular [Ca ⁺⁺ ]. Thus anything that increases intracellular [Ca ⁺⁺ ], including stretch of the afferent arteriole (myogenic control of renin secretion), angiotensin II (feedback inhibition), and endothelin, inhibits renin secretion. Renin release is also stimulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. Accordingly, anything that increases intracellular cAMP stimulates renin secretion, which includes norepinephrine acting through β-adrenergic receptors and prostaglandin E ₂ . Increases in intracellular cyclic guanosine monophosphate (cGMP) have been found to stimulate renin secretion in some situations and to inhibit secretion in others. Notably, two substances that increase intracellular cGMP are natriuretic peptides and nitric oxide. Nitric oxide stimulates renin secretion, whereas atrial natriuretic peptide and brain natriuretic peptide are inhibitory. The control of renin secretion by the macula densa (see Chapter 3 ) may involve paracrine factors such as prostaglandin E ₂ (which stimulates renin secretion when NaCl delivery to the macula densa is decreased) and adenosine (which inhibits renin secretion when NaCl delivery to the macular densa is increased).

Fig. 6.4 summarizes the essential components of the renin-angiotensin-aldosterone system . Renin alone does not have a physiologic function; it functions as a proteolytic enzyme. Its principal substrate is a circulating protein, angiotensinogen , which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10-amino-acid peptide, angiotensin I . Angiotensin I is further cleaved to an 8-amino-acid peptide, angiotensin II , by a converting enzyme ( angiotensin-converting enzyme [ACE] ) found on the surface of vascular endothelial cells. Pulmonary and renal endothelial cells are important sites for the bioconversion of angiotensin I to angiotensin II. ACE also degrades bradykinin, a potent vasodilator. Angiotensin II has several important physiologic functions, including the following:

• 1.
  

  Stimulation of aldosterone secretion by the adrenal cortex

  
  
• 2.
  

  Arteriolar vasoconstriction, which increases blood pressure

  
  
• 3.
  

  Stimulation of AVP secretion and thirst

  
  
• 4.
  

  Enhancement of NaCl reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, distal tubule, and collecting duct

Schematic representation of the essential components of the renin-angiotensin-aldosterone system. Activation of this system results in a decrease in the excretion of Na ⁺ and water by the kidneys. Note: Angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme, which is present on all vascular endothelial cells. As shown, the endothelial cells within the lungs play a significant role in this conversion process. AVP, Arginine vasopressin.

The effect on the proximal tubule is quantitatively the largest.

Angiotensin II is an important secretagogue for aldosterone . An increase in the plasma K ⁺ concentration is the other important stimulus for aldosterone secretion (see Chapter 7 ). Aldosterone is a steroid hormone produced by the glomerulosa cells of the adrenal cortex. Aldosterone acts in a number of ways on the kidneys (see Chapter 4 ). With regard to the regulation of the ECF volume, aldosterone reduces NaCl excretion by stimulating its reabsorption by several nephron segments. Most importantly it stimulates NaCl reabsorption in the aldosterone-sensitive distal nephron (ASDN) , which consists of the latter portion of the distal tubule and the collecting duct. To a lesser extent it also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop and the early portion of the distal tubule. ^a

Aldosterone has many cellular actions in the ASDN, including increasing the abundance and activity of ENaC in the apical membrane of principal cells and the abundance of Na ⁺ -K ⁺ –adenosine triphosphatase (ATPase) in the basolateral membrane of these same cells. As a result, Na ⁺ entry into the cell across the apical membrane is enhanced, as is its extrusion from the cell across the basolateral membrane. Thus net reabsorption of NaCl is increased (Cl ^– reabsorption is mostly passive and secondary to Na ⁺ reabsorption). Aldosterone also increases the abundance of the Na ⁺ -K ⁺ -2Cl ^– symporter in the thick ascending limb of Henle’s loop and the Na ⁺ -Cl ^– symporter in the early distal tubule (indirect effect), thereby stimulating NaCl reabsorption in these nephron segments.

Aldosterone selectivity and sensitivity are conferred by mineralocorticoid receptors present in cells in the ASDN, as well as by the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Because the mineralocorticoid receptor also binds glucocorticoids, 11β-HSD2 is required for aldosterone to specifically activate the mineralocorticoid receptor because it metabolizes glucocorticoids and thus prevents them from binding to the mineralocorticoid receptor.

In the Clinic

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