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Peritubular capillary blood

This pathway is referred to as transepithelial transport.

There are two types of tubular reabsorption:

Tubular reabsorption is considered passive when each of the steps in transepithelial transport takes place without the expenditure of energy. In other words, the movement of a given substance is from an area of high concentration to an area of low concentration by way of passive diffusion. Water is passively reabsorbed from the tubules back into the peritubular capillaries.

Active reabsorption occurs when the movement of a given substance across the luminal surface or the basolateral surface of the tubular epithelial cell requires energy. Substances that are actively reabsorbed from the tubule include glucose; amino acids; and Na+, PO4-3, and Ca++ ions. Three generalizations can be made regarding the tubular reabsorption of sodium, chloride, and water:

• Reabsorption of Na+ ions is an active process; 80% of the total energy expended by the kidneys is used for sodium transport out of the tubular epithelial cell.

• Reabsorption of Cl- ions is a passive process; Cl- ions are reabsorbed according to the electrical gradient created by the reabsorption of Na+ ions.

• Reabsorption of water is a passive process; water is reabsorbed according to the osmotic gradient created by reabsorption of Na+ ions.

In other words, when sodium is reabsorbed, chloride and water follow it.

Sodium reabsorption. Sodium is reabsorbed by different mechanisms as the filtrate progresses through the tubule. Sodium ions leave the filtrate and enter the tubular epithelial cell by way of the following processes (see Figure 19.4):

• Na+-glucose, Na+-amino acid, Na+-phosphate, and Na+-lactate sym-porter mechanisms; Na+-H+ antiporter mechanism: first half of the proximal tubule

• Coupled with Cl- reabsorption by way of transcellular (through the epithelial cell) and paracellular (in between the epithelial cells) pathways: second half of the proximal tubule

Figure 19.4 Tubular reabsorption of sodium. Sodium ions are actively transported out of the tubular epithelial cell through the basolateral membrane by the Na K+-ATPase pump. These ions then passively diffuse from interstitial fluid into blood of the peritubular capillaries. The active removal of Na + ions from the tubular epithelial cells establishes a concentration gradient for passive diffusion of Na + ions into cells from the tubular lumen. Potassium ions actively transported into epithelial cells of the proximal tubule as a result of this process simply diffuse back into interstitial fluid through channels located in the basolateral membrane. In the distal tubule and collecting duct, the K + ions diffuse through channels in the luminal membrane into the tubular fluid and are excreted in the lumen. The diffusion of sodium may be coupled to reabsorption of organic molecules such as glucose or amino acids in the proximal tubule and the Loop of Henle. It may also occur through Na + channels in the distal tubule and collecting duct.

Figure 19.4 Tubular reabsorption of sodium. Sodium ions are actively transported out of the tubular epithelial cell through the basolateral membrane by the Na K+-ATPase pump. These ions then passively diffuse from interstitial fluid into blood of the peritubular capillaries. The active removal of Na + ions from the tubular epithelial cells establishes a concentration gradient for passive diffusion of Na + ions into cells from the tubular lumen. Potassium ions actively transported into epithelial cells of the proximal tubule as a result of this process simply diffuse back into interstitial fluid through channels located in the basolateral membrane. In the distal tubule and collecting duct, the K + ions diffuse through channels in the luminal membrane into the tubular fluid and are excreted in the lumen. The diffusion of sodium may be coupled to reabsorption of organic molecules such as glucose or amino acids in the proximal tubule and the Loop of Henle. It may also occur through Na + channels in the distal tubule and collecting duct.

• Na+, K+, 2Cl- symporter mechanism: ascending limb of the Loop of Henle

• Na+, Cl- symporter mechanism: distal tubule

• Na+ channels: distal tubule, collecting duct

More simply, in the early regions of the tubule (proximal tubule and Loop of Henle), Na+ ions leave the lumen and enter the tubular epithelial cells by way of passive facilitated transport mechanisms. The diffusion of Na+ ions is coupled with organic molecules or with other ions that electrically balance the flux of these positively charged ions. In the latter regions of the tubule (distal tubule and collecting duct), Na+ ions diffuse into the epithelial cells through Na+ channels.

An essential requirement for diffusion of Na+ ions is the creation of a concentration gradient for sodium between the filtrate and intracellular fluid of the epithelial cells. This is accomplished by the active transport of Na+ ions through the basolateral membrane of the epithelial cells (see Figure 19.4). Sodium is moved across this basolateral membrane and into the interstitial fluid surrounding the tubule by the Na+, K+-ATPase pump. As a result, the concentration of Na+ ions within the epithelial cells is reduced, facilitating the diffusion of Na+ ions into the cells across the luminal membrane. Potassium ions transported into the epithelial cells as a result of this pump diffuse back into the interstitial fluid (proximal tubule and Loop of Henle) or into the tubular lumen for excretion in the urine (distal tubule and collecting duct).

The amount of sodium reabsorbed from the proximal tubule and the Loop of Henle is held constant:

• Proximal tubule: 65% of the filtered sodium is reabsorbed

• Ascending limb of the Loop of Henle: 25% of the filtered sodium is reabsorbed

This reabsorption occurs regardless of the sodium content of the body. In order to make adjustments in the sodium load, the reabsorption of the remaining 10% of filtered Na+ ions from the distal tubule and collecting duct is physiologically controlled by two hormones:

• Aldosterone

• Atrial natriuretic peptide

Aldosterone released from the adrenal cortex promotes the reabsorption of sodium from the distal tubule and collecting duct. The mechanisms of action of aldosterone include:

• Formation of Na+ channels in the luminal membrane of the tubular epithelial cells (facilitates passive diffusion of Na+ ions into the cell)

• Formation of Na+, K+-ATPase carrier molecules in the basolateral membrane of the tubular epithelial cells (promotes extrusion of Na+ ions from the cells and their movement into plasma by way of per-itubular capillaries; enhances the concentration gradient for passive diffusion through Na+ channels in the luminal membrane)

Atrial natriuretic peptide (ANP) released from myocardial cells in the atria of the heart inhibits the reabsorption of sodium from the collecting duct. The mechanisms of action of ANP include:

• Inhibition of aldosterone secretion

• Inhibition of Na+ channels in the luminal membrane of the tubular epithelial cells

Recall that the reabsorption of Na+ ions is accompanied by reabsorption of Cl- ions, which diffuse down their electrical gradient, and by reabsorption of water, which diffuses down its osmotic gradient. The net result is an expansion of plasma volume and consequently an increase in blood pressure. Therefore, the regulation of sodium reabsorption is important in the long-term regulation of blood pressure. As such, aldosterone and ANP, as well as the factors involved in their release, are discussed further in subsequent sections.

Chloride reabsorption. Chloride ions are reabsorbed passively according to the electrical gradient established by the active reabsorption of sodium. Chloride ions move from the tubular lumen back into the plasma by two pathways:

• Transcellular; through the tubular epithelial cells

• Paracellular; in-between the tubular epithelial cells

Most of the Cl- ions diffuse between the tubular epithelial cells.

Water reabsorption. Water is reabsorbed passively by way of osmosis from many regions of the tubule. As with sodium and chloride, 65% of the filtered water is reabsorbed from the proximal tubule. An additional 15% of the filtered water is reabsorbed from the descending limb of the Loop of Henle. This reabsorption occurs regardless of the water content of the body. The water enters the tubular epithelial cells through water channels, also referred to as aquaporins. These channels are always open in the early regions of the tubule.

In order to make adjustments in the water load, the reabsorption of the remaining 20% of the filtered water from the distal tubule and the collecting duct is physiologically controlled by antidiuretic hormone (ADH), also referred to as vasopressin. Antidiuretic hormone, synthesized in the hypothalamus and released from the neurohypophysis of the pituitary gland, promotes the reabsorption of water from the distal tubule and collecting duct. The mechanism of action of ADH involves an increase in permeability of the water channels in the luminal membrane of tubular epithelial cells. Water diffuses into these cells and is ultimately reabsorbed into the plasma by way of the peritubular capillaries.

Recall that reabsorption of water is important in the regulation of plasma osmolarity. As the levels of ADH increase and more water is reabsorbed from the kidneys, the plasma is diluted and plasma osmolarity decreases. Conversely, as the levels of ADH decrease and more water is lost in the urine, plasma becomes more concentrated and plasma osmolarity increases. Factors involved in the release of ADH are discussed further in subsequent sections.

Production of urine of varying concentrations. In order to regulate plasma volume and osmolarity effectively, the kidneys must be able to alter the volume and concentration of the urine that is eliminated. Accordingly, the concentration of urine may be varied over a very wide range depending upon the body's level of hydration. The most dilute urine produced by the kidneys is 65 to 70 mOsm/l (when the body is overhydrated) and the most concentrated urine is 1200 mOsm/l (when the body is dehydrated). (Recall that plasma osmolarity is 290 to 300 mOsm/l.)

An essential factor in the ability to excrete urine of varying concentrations is the presence of a vertical osmotic gradient in the medullary region of the kidney (see Figure 19.5). The osmolarity of the interstitial fluid in the cortical region of the kidney is about 300 mOsm/l; however, the osmolarity of interstitial fluid in the medulla increases progressively, from 300 mOsm/ l in the outer region near the cortex to 1200 mOsm/l in the innermost region of the medulla. The increase in osmolarity is due to the accumulation of Na+ and Cl- ions in the interstitial fluid. This vertical osmotic gradient is created by the Loops of Henle of the juxtamedullary nephrons. Recall that the Loop of Henle in these nephrons penetrates deeply into the medulla. The gradient is then utilized by the collecting ducts, along with ADH, to alter the concentration of urine. The following is a summary of the reabsorption of sodium, chloride, and water by each region of the nephron.

Plasma is freely filtered from the glomerulus so that everything in the plasma, except for the plasma proteins, is filtered. Therefore, the initial osmolarity of the filtrate is no different from that of the plasma and is about 300 mOsm/l (see Figure 19.5). Approximately 125 ml/min of the plasma is filtered. As the filtrate flows through the proximal tubule, 65% of the filtered Na+ ions are actively reabsorbed, and 65% of the filtered Cl- ions and water are passively reabsorbed. Because the water follows the sodium by way of osmosis, no change takes place in the osmolarity of the filtrate — only a change in volume. At the end of the proximal tubule, approximately 44 ml of filtrate with an osmolarity of 300 mOsm/l remain in the tubule.

The descending limb of the Loop of Henle is permeable to water only. As this region of the tubule passes deeper into the medulla, water leaves the filtrate down its osmotic gradient until it equilibrates with the increasingly concentrated interstitial fluid (see Figure 19.5). As a result, the filtrate also

Bowman's capsule

Proximal tubule

Bowman's capsule

Proximal tubule

Distal tubule

65-70

CORTEX

NaCl

Horizontal osmotic gradient

Vertical osmotic gradient

1200

NaCl

NaCl

Loop of Henle

NaCl

MEDULLA

Collecting duct 1200 1200

Loop of Henle

Figure 19.5 Production of varying concentrations of urine. The kidneys are capable of producing urine as diluted as 65 to 70 mOsm/l and as concentrated as 1200 mOsm/l. The concentration of urine is determined by the body's level of hydration. Sodium ions are actively transported from the ascending limb of the Loop of Henle into interstitial fluid —an active process used to accumulate Na + and Cl-ions in the medulla. As a result, a vertical osmotic gradient is established in which interstitial fluid becomes increasingly concentrated. This gradient is necessary for reabsorption of water from the collecting duct. Furthermore, a horizontal osmotic gradient of 200 mOsm/l is developed between filtrate of the ascending limb of the Loop of Henle and interstitial fluid. Consequently, osmolarity of the filtrate at the end of the Loop of Henle is 100 mOsm/l and the kidney may now excrete a urine significantly more diluted than plasma. In this way, when the body is overhydrated, excess water is eliminated. The presence of aldosterone promotes additional reabsorption of Na + ions from the distal tubule and collecting duct, further diluting the filtrate to 65 to 70 mOsm/l. The presence of ADH promotes reabsorption of water from the distal tubule and collecting duct. Water diffuses out of the collecting duct down its concentration gradient into interstitial fluid. High levels of ADH may concentrate the filtrate to 1200 mOsm/l so that, when the body is dehydrated, water is conserved.

becomes increasingly concentrated. At the tip of the Loop of Henle, the filtrate has an osmolarity of 1200 mOsm/l.

The ascending limb of the Loop of Henle is permeable to NaCl only. As the filtrate flows upward through this region of the tubule back toward the cortex, Na+ ions are continuously and actively pumped out of the filtrate and into the interstitial fluid; chloride ions passively follow the sodium. As a result, the filtrate becomes increasingly dilute. At the end of the ascending limb of the Loop of Henle, approximately 25 ml of filtrate with an osmolarity of 100 mOsm/l remain in the tubule.

Because the transport of sodium is an active process, it is used to accumulate NaCl in the interstitial fluid of the medulla. In fact, this activity is involved in the initial establishment of the vertical osmotic gradient. Furthermore, sodium is actively transported out of the tubular epithelial cells up its concentration gradient until the filtrate is 200 mOsm/l less concentrated than the surrounding interstitial fluid. This difference between the filtrate and the interstitial fluid is referred to as the horizontal osmotic gradient. Because the filtrate at the end of the Loop of Henle has an osmolarity of 100 mOsm/l, the kidneys have the ability to produce urine that is significantly more dilute than the plasma.

As the filtrate progresses through the distal tubule and the collecting duct, the remaining NaCl (10% of that which was filtered) and water (20% of that filtered) are handled. As discussed, the presence of aldosterone enhances the reabsorption of sodium from these regions. Consequently, the filtrate becomes as dilute as 65 to 70 mOsm/l. The presence of ADH enhances the reabsorption of water from these regions; in particular, as the filtrate flows through the collecting duct, it enters a region of increasing osmolarity. The increased permeability of water due to ADH allows it to diffuse out of the collecting duct and into the interstitial fluid down its concentration gradient. When the levels of ADH are high, the water may continue to leave the tubule until the filtrate equilibrates with the surrounding interstitial fluid. In this case, the filtrate becomes as concentrated as 1200 mOsm/l and a small volume of urine is produced. When the levels of ADH are low, water remains in the collecting duct and a large volume of urine is produced.

Pharmacy application: physiological action of diuretics

Diuretics are drugs that cause an increase in urine output. It is important to note that, except for the osmotic diuretics, these drugs typically enhance the excretion of solute and water. Therefore, the net effect of most diuretics is to decrease plasma volume, but cause little change in plasma osmolarity. Five classes of diuretics and their major sites of action are:

• Osmotic diuretics: proximal tubule and descending limb of the Loop of Henle

• Loop diuretics: ascending limb of the Loop of Henle

• Thiazide diuretics: distal tubule

• Potassium-sparing diuretics: cortical collecting duct

• Carbonic anhydrase inhibitors: proximal tubule

Osmotic diuretics such as mannitol act on the proximal tubule and, in particular, the descending limb of the Loop of Henle — portions of the tubule permeable to water. These drugs are freely filtered at the glomerulus, but not reabsorbed; therefore, the drug remains in the tubular filtrate, increasing the osmolarity of this fluid. This increase in osmolarity keeps the water within the tubule, causing water diuresis. Because they primarily affect water and not sodium, the net effect is a reduction in total body water content more than cation content. Osmotic diuretics are poorly absorbed and must be administered intravenously. These drugs may be used to treat patients in acute renal failure and with dialysis disequilibrium syndrome. The latter disorder is caused by the excessively rapid removal of solutes from the extracellular fluid by hemodialysis.

Loop diuretics such as furosemide act on the ascending limb of the Loop of Henle, a portion of the tubule permeable to sodium and chloride. The mechanism of action of these diuretics involves inhibition of the Na+, K+, 2Cl- symporter in the luminal membrane. By inhibiting this transport mechanism, loop diuretics reduce the reabsorption of NaCl and K+ ions. Recall that reabsorption of NaCl from the ascending limb of the Loop of Henle generates and maintains the vertical osmotic gradient in the medulla. Without the reabsorption of NaCl, this gradient is lost and the osmolarity of the interstitial fluid in the medulla is decreased. When the osmolarity of the medulla is decreased, the reabsorption of water from the descending limb of the Loop of Henle and the collecting duct is significantly reduced. The net result of the loop diuretics includes reduced NaCl and water reabsorption and, therefore, enhanced NaCl and water loss in the urine. The most potent diuretics available (up to 25% of the filtered Na+ ions may be excreted) — the loop diuretics — may cause hypovolemia. These drugs are often used to treat acute pulmonary edema, chronic congestive heart failure, and the edema and ascites of liver cirrhosis.

Thiazide diuretics such as chlorothiazide act on the distal tubule, a portion of the tubule that is permeable to sodium. The mechanism of action of these diuretics involves inhibition of NaCl reabsorption by blocking the Na+, Cl- symporter in the luminal membrane. The thiazide diuretics are only moderately effective due to the location of their site of action. Approximately 90% of the filtered Na+ ions have already been reabsorbed when the filtrate reaches the distal tubule. These drugs may be used for treatment of edema associated with heart, liver, and renal disease. Thiazide diuretics are also widely used for the treatment of hypertension.

Potassium-sparing diuretics act on the late portion of the distal tubule and on the cortical collecting duct. As a result of their site of action, these diuretics also have a limited effect on diuresis compared to the loop diuretics (3% of the filtered Na+ ions may be excreted). However, the clinical advantage of these drugs is that the reabsorption of K+ ions is enhanced, reducing the risk of hypokalemia.

Two types of potassium-sparing diuretics have different mechanisms of action. Agents of the first type, which include spirono-lactone, are also known as aldosterone antagonists. These drugs bind directly to the aldosterone receptor and prevent this hormone from exerting its effects. Agents of the second type, which include amiloride, are inhibitors of the tubular epithelial Na+ channels. Acting on the Na+ channels in the luminal membrane, these drugs prevent movement of Na+ ions from the filtrate into the epithelial cell. Because this transport of Na+ ions into the cell is coupled to the transport of K+ ions out of the cell, less potassium is lost to the filtrate and therefore the urine.

Potassium-sparing diuretics are often coadministered with thi-azide or loop diuretics in the treatment of edema and hypertension. In this way, edema fluid is lost to the urine while K+ ion balance is better maintained. The aldosterone antagonists are particularly useful in the treatment of primary hyperaldosteronism.

Carbonic anhydrase inhibitors such as acetazolamide act in the proximal tubule. These drugs prevent the formation of H+ ions, which are transported out of the tubular epithelial cell in exchange for Na+ ions. These agents have limited clinical usefulness because they result in development of metabolic acidosis.

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Essentials of Human Physiology

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