Berne and Levy Physiology, 6th ed

33. Solute and Water Transport along the Nephron: Tubular Function

 

The formation of urine involves three basic processes: (1) ultrafiltration of plasma by the glomerulus, (2) reabsorption of water and solutes from the ultrafiltrate, and (3) secretion of selected solutes into tubular fluid. Although an average of 115 to 180 L/day in women and 130 to 200 L/day in men of essentially protein-free fluid is filtered by the human glomeruli each day,* less than 1% of the filtered water and sodium chloride (NaCl) and variable amounts of other solutes are excreted in urine (Table 33-1). By the processes of reabsorption and secretion, the renal tubules modulate the volume and composition of urine (Table 33-2), which in turn allows the tubules to precisely control the volume, osmolality, composition, and pH of the extracellular and intracellular fluid compartments. Transport proteins in cell membranes of the nephron mediate the reabsorption and secretion of solutes and water in the kidneys. Approximately 5% to 10% of all human genes code for transport proteins, and genetic and acquired defects in transport proteins are the cause of many kidney diseases (Table 33-3). In addition, numerous transport proteins are important drug targets. This chapter discusses NaCl and water reabsorption, transport of organic anions and cations, the transport proteins involved in solute and water transport, and some of the factors and hormones that regulate NaCl transport. Details on acid-base transport and on K+, Ca++, and inorganic phosphate (Pi) transport and their regulation are provided in Chapters 34 through 36.

 

SOLUTE AND WATER REABSORPTION ALONG THE NEPHRON

 

The general principles of solute and water transport across epithelial cells were discussed in Chapter 1.

 

Quantitatively, reabsorption of NaCl and water represents the major function of nephrons. Approximately 25,000 mEq/day of Na+ and 179 L/day of water are reabsorbed by the renal tubules (Table 33-1). In addition, renal transport of many other important solutes is linked either directly or indirectly to reabsorption of Na+. In the following sections, the NaCl and water transport processes of each nephron segment and their regulation by hormones and other factors are presented.

 

Proximal Tubule

 

The proximal tubule reabsorbs approximately 67% of filtered water, Na+, Cl-, K+, and other solutes. In addition, the proximal tubule reabsorbs virtually all the glucose and amino acids filtered by the glomerulus. The key element in proximal tubule reabsorption is Na+,K+-ATPase in the basolateral membrane. Reabsorption of every substance, including water, is linked in some manner to the operation of Na+,K+-ATPase.

 

Na+ Reabsorption

 

Na+ is reabsorbed by different mechanisms in the first and the second halves of the proximal tubule. In the first half of the proximal tubule, Na+ is reabsorbed primarily with bicarbonate (HCO3-) and a number of other solutes (e.g., glucose, amino acids, Pi, lactate). In contrast, in the second half, Na+ is reabsorbed mainly with Cl-. This disparity is mediated by differences in the Na+ transport systems in the first and second halves of the proximal tubule and by differences in the composition of tubular fluid at these sites.

 

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Table 33-1. Filtration, Excretion, and Reabsorption of Water, Electrolytes, and Solutes by the Kidneys

 

Substance

Measure

Filtered*

Excreted

Reabsorbed

% Filtered Load Reabsorbed

Water

L/day

180

1.5

178.5

99.2

Na+

mEq/day

25,200

150

25,050

99.4

K+

mEq/day

720

100

620

86.1

Ca++

mEq/day

540

10

530

98.2

HCO3-

mEq/day

4320

2

4318

99.9+

Cl-

mEq/day

18,000

150

17,850

99.2

Glucose

mmol/day

800

0

800

100.0

Urea

g/day

56

28

28

50.0

 

*The filtered amount of any substance is calculated by multiplying the concentration of that substance in the ultrafiltrate by the glomerular filtration rate (GFR); for example, the filtered load of Na+ is calculated as [Na+]ultrafiltrate (140 mEq/L) × GFR (180 L/day) =25,200 mEq/day.

 

 

 

Table 33-2. Composition of Urine

 

Substance

Concentration

Na+

50-130 mEq/L

K+

20-70 mEq/L

Ammonium (NH4+)

30-50 mEq/L

Ca++

5-12 mEq/L

Mg++

2-18 mEq/L

Cl-

50-130 mEq/L

Inorganic phosphate (Pi)

20-40 mEq/L

Urea

200-400 mM

Creatinine

6-20 mM

pH

5.0-7.0

Osmolality

500-800 mOsm/kg H2O

Glucose

0

Amino acids

0

Protein

0

Blood

0

Ketones

0

Leukocytes

0

Bilirubin

0

 
 

 


The composition and volume of urine can vary widely in the healthy state. These values represent average ranges. Water excretion ranges between 0.5 and 1.5 L/day.
Data from Valtin HV: Renal Physiology, 2nd ed. Boston, Little, Brown, 1983.

 

In the first half of the proximal tubule, Na+ uptake into the cell is coupled with either H+ or organic solutes (Fig. 33-1). Specific transport proteins mediate entry of Na+ into the cell across the apical membrane. For example, the Na+-H+ antiporter (Fig. 33-1, A) couples entry of Na+ with extrusion of H+ from the cell. H+ secretion results in reabsorption of sodium bicarbonate (NaHCO3) (see Chapter 36). Na+ also enters proximal cells via several symporter mechanisms, including Na+-glucose, Na+-amino acid, Na+-Pi, and Na+-lactate (Fig. 33-1, B). The glucose and other organic solutes that enter the cell with Na+ leave the cell across the basolateral membrane via passive transport mechanisms. Any Na+ that enters the cell across the apical membrane leaves the cell and enters the blood via Na+,K+-ATPase. In brief, reabsorption of Na+ in the first half of the proximal tubule is coupled to that of HCO3- and a number of organic molecules. Reabsorption of many organic molecules is so avid that they are almost completely removed from the tubular fluid in the first half of the proximal tubule (Fig. 33-2). Reabsorption of NaHCO3 and Na+-organic solutes across the proximal tubule establishes a transtubular osmotic gradient (i.e., the osmolality of the interstitial fluid bathing the basolateral side of the cells is higher than the osmolality of tubule fluid) that provides the driving force for the passive reabsorption of water by osmosis. Because more water than Cl-is reabsorbed in the first half of the proximal tubule, the [Cl-] in tubular fluid rises along the length of the proximal tubule (Fig. 33-2).

 

In the second half of the proximal tubule, Na+ is mainly reabsorbed with Cl- across both the transcellular and paracellular pathways (Fig. 33-3). Na+ is primarily reabsorbed with Cl- rather than organic solutes or HCO3- as the accompanying anion because the Na+ transport mechanisms in the second half of the proximal tubule differ from those in the first half. Furthermore, the tubular fluid that enters the second half contains very little glucose and amino acids, but the high [Cl-] (140 mEq/L) in tubule fluid exceeds that in the first half (105 mEq/L). The high [Cl-] is due to the preferential reabsorption of Na+ with HCO3- and organic solutes in the first half of the proximal tubule.

 

IN THE CLINIC

 

Fanconi's syndrome, a renal disease that is either hereditary or acquired, results from an impaired ability of the proximal tubule to reabsorb HCO3-, Pi, amino acids, glucose, and low-molecular-weight proteins. Because other segments of the nephron cannot reabsorb these solutes and protein, Fanconi's syndrome results in increased urinary excretion of HCO3-, amino acids, glucose, Pi, and low-molecular-weight proteins.

 

 

The mechanism of transcellular Na+ reabsorption in the second half of the proximal tubule is shown in Figure 33-3. Na+ enters the cell across the luminal membrane primarily via the parallel operation of an Na+-H+ antiporter and one or more Cl--anion antiporters. Because the secreted H+ and anion combine in the tubular fluid and reenter the cell, operation of the Na+-H+ and Cl--anion antiporters is equivalent to uptake of NaCl from tubular fluid into the cell. Na+ leaves the cell via Na+,K+-ATPase, and Cl- leaves the cell and enters the blood via a K+-Cl- symporter in the basolateral membrane.

 

NaCl is also reabsorbed across the second half of the proximal tubule via a paracellular route. Paracellular NaCl reabsorption occurs because the rise in [Cl-] in tubule fluid in the first half of the proximal tubule creates a [Cl-] gradient (140 mEq/L in the tubule lumen and 105 mEq/L in the interstitium). This concentration gradient favors diffusion of Cl- from the tubular lumen across the tight junctions into the lateral intercellular space. Movement of the negatively charged Cl- results in the tubular fluid becoming positively charged relative to blood. This positive transepithelial voltage causes the diffusion of positively charged Na+ out of the tubular fluid across the tight junction into blood. Thus, in the second half of the proximal tubule, some Na+ and Cl- are reabsorbed across the tight junctions via passive diffusion. Reabsorption of NaCl establishes a transtubular osmotic gradient that provides the driving force for the passive reabsorption of water by osmosis.

 

In summary, reabsorption of Na+ and Cl- in the proximal tubule occurs across paracellular and transcellular pathways. Approximately 67% of the NaCl filtered each day is reabsorbed in the proximal tubule. Of this, two thirds moves across the transcellular pathway, whereas the remaining third moves across the paracellular pathway (Table 33-4).

 

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Table 33-3. Some Monogenic Renal Diseases Involving Transport Proteins

 

Diseases

Mode of Inheritance

Gene

Transport Protein*

Nephron Segment

Phenotype

Cystinuria, type I

AR

SLC3A1, also known as D2/rBAT

Basic amino acid transporter

Proximal tubule

Increased excretion of basic amino acids, nephrolithiasis (kidney stones)

Cystinuria, types I and III

IAR

SLC7A9, also known as b°, +AT

B°+AT

Proximal tubule

Increased excretion of basic amino acids, nephrolithiasis

Proximal renal tubular acidosis

AR

SLC4A4, also known as NBCe1

Na+-HCO3- symporter

Proximal tubule

Hyperchloremic metabolic acidosis

X-linked nephrolithiasis (Dent's disease)

XLR

CLC5, also known as ClC-5

Cl- channel

Distal tubule

Hypercalciuria, nephrolithiasis

Bartter's syndrome

AR type I

SLC12A1, also known as NKCC2

1Na+-1K+-2Cl- symporter (furosemide sensitive)

TAL

Hypokalemia, metabolic alkalosis, hyperaldosteronism

 

AR type II

KCNJ1, also known as ROMK

K+ channel

TAL

Hypokalemia, metabolic alkalosis, hyperaldosteronism

 

AR type III

CLCNKB

Cl- channel (basolateral membrane)

TAL

Hypokalemia, metabolic alkalosis, hyperaldosteronism

 

AR type IV

BSND, also known as barttin

Cl- channel (barttin recruits CLCNKB to the basolateral membrane)

TAL

Hypokalemia, metabolic alkalosis, hyperaldosteronism

Hypomagnesemia-hypercalciuria syndrome

AR

CLDN16

Claudin-16, also known as paracellin 1

TAL

Hypomagnesemia, hypercalciuria, nephrolithiasis

Gitelman's syndrome

AR

SLC12A3, also known as NCC/TSC

Thiazide-sensitive symporter

Distal tubule

Hypomagnesemia, hypokalemic metabolic alkalosis, hypocalciuria, hypotension

Pseudohypoaldosteronism

AR

SCNN1A, SCNN1B, and SCNN1G, also known as α-ENaC, β-ENaC and γ-ENaC

α, β, and γ subunit of amiloride-sensitive Na+channel

Collecting duct

Increased excretion of Na+, hyperkalemia, hypotension

 

AD

MR

Mineralocorticoid receptor

Collecting duct

Increased excretion of Na+, hyperkalemia, hypotension

Liddle's syndrome

AD

SCNN1B, SCNN1G, also known as β-ENaC and γ-ENaC

β and γ subunits of amiloride-sensitive Na+channel

Collecting duct

Decreased excretion of Na+, hypertension

Nephrogenic diabetes insipidus

AR

AQP2

Aquaporin-2 water channel

Collecting duct

Polyuria, polydipsia, plasma hyperosmolality

Distal renal tubular acidosis

AD/AR

SLC4A1, also known as AE1

Cl--HCO3- antiporter

Collecting duct

Metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis

 

AR

ATP6V1B1

Subunit of H+-ATPase

Collecting duct

Metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis

 

AR

ATP6V0A4

Accessory subunit of H+-ATPase

Collecting duct

Metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis

 

 


*There are 40 different solute transporter families that form the so-called SLC (solute carrier) series.
AD, autosomal dominant; AR, autosomal recessive; IAR, incomplete autosomal recessive; TAL, thick ascending limb of Henle's loop; XLR, X-linked recessive. Data from Guay-Woodford LM: Semin Nephrol 19:312, 1999.

 

Water Reabsorption

 

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Figure 33-1 Na+ transport processes in the first half of the proximal tubule. These transport mechanisms are present in all cells in the first half of the proximal tubule but are separated into different cells to simplify the discussion. A, Operation of the Na+-H+ antiporter (NHE3) in the apical membrane and the Na+,K+-ATPase and HCO3- transporters, including the Cl--HCO3- antiporter (AE2) and the 1Na+-3HCO3- symporter (NBC1; see also Chapter 36) in the basolateral membrane mediates reabsorption of NaHCO3. Note that a single HCO3- transporter is illustrated for simplicity. Carbon dioxide and water combine inside the cells to form H+ and HCO3- in a reaction facilitated by the enzyme carbonic anhydrase (CA). B, Operation of the Na+-glucose symporter (SGLT2) in the apical membrane, in conjunction with Na+,K+-ATPase and the glucose transporter (GLUT2) in the basolateral membrane, mediates Na+-glucose reabsorption. Inactivating mutations in the GLUT2 gene lead to decreased glucose reabsorption in the proximal tubule and glucosuria (i.e., glucose in the urine). Though not shown, Na+ reabsorption is also coupled with other solutes, including amino acids, Pi, and lactate. Reabsorption of these solutes is mediated by the Na+-amino acid, Na+-Pi, and Na+-lactate symporters located in the apical membrane and the Na+,K+-ATPase, amino acid, Pi and lactate transporters located in the basolateral membrane. Three classes of amino acid transporters have been identified in the proximal tubule: two that transport Na+ in conjunction with either acidic or basic amino acids and one that does not require Na+ and transports basic amino acids.

 

 

 

Figure 33-2 Concentration of solutes in tubule fluid as a function of length along the proximal tubule. [TF] is the concentration of the substance in tubular fluid; [P] is the concentration of the substance in plasma. Values above 100 indicate that relatively less of the solute than water was reabsorbed, and values below 100 indicate that relatively more of the substance than water was reabsorbed.

 

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Figure 33-3 Na+ transport processes in the second half of the proximal tubule. Na+ and Cl- enter the cell across the apical membrane via the operation of parallel Na+-H+ and Cl--anion antiporters. More than one Cl--anion antiporter may be involved in this process, but only one is depicted. The secreted H+ and anion combine in the tubular fluid to form an H+-anion complex that can recycle across the plasma membrane. Accumulation of the H+-anion complex in tubular fluid establishes an H+-anion concentration gradient that favors H+-anion recycling across the apical plasma membrane into the cell. Inside the cell, H+ and the anion dissociate and recycle back across the apical plasma membrane. The net result is uptake of NaCl across the apical membrane. The anion may be hydroxide ions (OH-), formate (HCO2-), oxalate, HCO3-, or sulfate. The positive transepithelial voltage in the lumen, indicated by the plus sign inside the circle in the tubular lumen, is generated by diffusion of Cl- (lumen to blood) across the tight junction. The high [Cl-] of tubular fluid provides the driving force for diffusion of Cl-. Some glucose is also reabsorbed in the second half of the proximal tubule by a mechanism similar to that described in the first half of the proximal tubule, except that the Na+-glucose symporter (SGLT1 gene) transports 2Na+ with one glucose and has higher affinity and lower capacity than the Na+-glucose symporter in the first part of the proximal tubule (i.e., SGLT2). In addition, glucose exits the cell across the basolateral membrane via GLUT1 rather than via GLUT2 as in the first part of the proximal tubule.

 

 

 

Table 33-4. NaCl Transport along the Nephron

 

Segment

Percentage of Filtrate Reabsorbed

Mechanism of Na+ Entry across the Apical Membrane

Major Regulatory Hormones

Proximal tubule

67%

Na+-H+ antiporter, Na+ symporter with amino acids and organic solutes, 1Na+-1H+-2Cl--anion antiporter, paracellular

Angiotensin II
Norepinephrine
Epinephrine
Dopamine

Loop of Henle

25%

1Na+-1K+-2Cl- symporter

Aldosterone
Angiotensin II

Distal tubule

≈5%

NaCl symporter (early)
Na+ channels (late)

Aldosterone
Angiotensin II

Collecting duct

≈3%

Na+ channels

Aldosterone, ANP, BNP, urodilatin, uroguanylin, guanylin, angiotensin II

 

 

 

 

 

Table 33-5. Water Transport along the Nephron

 

Segment

Percentage of Filtrate Reabsorbed

Mechanism of Water Reabsorption

Hormones That Regulate Water Permeability

Proximal tubule

67%

Passive

None

Loop of Henle

15%

Descending thin limb only; passive

None

Distal tubule

0%

No water reabsorption

None

Late distal tubule and collecting duct

≈8%-17%

Passive

ADH, ANP, BNP*

 


*Atrial and brain natriuretic peptides inhibit antidiuretic hormone-stimulated water permeability.

 

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Figure 33-4 Routes of reabsorption of water and solute across the proximal tubule. Transport of solutes, including Na+, Cl-, and organic solutes, into the lateral intercellular space increases the osmolality of this compartment, which establishes the driving force for osmotic reabsorption of water across the proximal tubule. This occurs because some Na+,K+-ATPase and some transporters of organic solutes, HCO3-, and Cl- are located on the lateral cell membranes and deposit these solutes between cells. Furthermore, some NaCl also enters the lateral intercellular space via diffusion across the tight junction (i.e., paracellular pathway). An important consequence of osmotic water flow across the transcellular and paracellular pathways in the proximal tubule is that some solutes, especially K+ and Ca++, are entrained in the reabsorbed fluid and thereby reabsorbed by the process of solvent drag.

 

The proximal tubule reabsorbs 67% of the filtered water (Table 33-5). The driving force for water reabsorption is a transtubular osmotic gradient established by reabsorption of solute (e.g., NaCl, Na+-glucose). Reabsorption of Na+ along with organic solutes, HCO3-, and Cl- from tubular fluid into the lateral intercellular spaces reduces the osmolality of the tubular fluid and increases the osmolality of the lateral intercellular space (Fig. 33-4). Because the proximal tubule is highly permeable to water, water is reabsorbed via osmosis. Because the apical and basolateral membranes of proximal tubule cells express aquaporin water channels, water is primarily reabsorbed across the proximal tubular cells. Some water is also reabsorbed across the tight junctions. The accumulation of fluid and solutes within the lateral intercellular space increases hydrostatic pressure in this compartment. The increased hydrostatic pressure forces fluid and solutes into the capillaries.* Thus, water reabsorption follows solute reabsorption in the proximal tubule. The reabsorbed fluid is slightly hyperosmotic relative to plasma. However, this difference in osmolality is so small that it is commonly said that proximal tubule reabsorption is isosmotic (i.e., 67% of the filtered load of solute and water is reabsorbed). Indeed, there is little difference in the osmolality of tubular fluid at the start and end of the proximal tubule. An important consequence of osmotic water flow across the proximal tubule is that some solutes, especially K+ and Ca++, are entrained in the reabsorbed fluid and thereby reabsorbed by the process of solvent drag (Fig. 33-4). Reabsorption of virtually all organic solutes, Cl- and other ions, and water is coupled to Na+ reabsorption. Therefore, changes in Na+ reabsorption influence the reabsorption of water and other solutes by the proximal tubule.

 

Protein Reabsorption

 

Proteins filtered by the glomerulus are reabsorbed in the proximal tubule. As mentioned previously, peptide hormones, small proteins, and small amounts of large proteins such as albumin are filtered by the glomerulus. Overall, only a small percentage of proteins cross the glomerulus and enter Bowman's space (i.e., the concentration of proteins in the glomerular ultrafiltrate is only 40 mg/L). However, the amount of protein filtered per day is significant because the glomerular filtration rate (GFR) is so high:

 

 

 

Table 33-6. Some Organic Anions Secreted by the Proximal Tubule

 

Endogenous Anions

Drugs

cAMP, cGMP
Bile salts
Hippurates
Oxalate
Prostaglandins: PGE2, PGF
Urate
Vitamins: ascorbate, folate

Acetazolamide
Chlorothiazide
Furosemide
Penicillin
Probenecid
Salicylate (aspirin)
Hydrochlorothiazide
Bumetanide
Nonsteroidal antiinflammatory drugs (NSAIDs):
Indomethacin

 

 

 

Proteins undergo endocytosis either intact or after being partially degraded by enzymes on the surface of proximal tubule cells. Once the proteins and peptides are inside the cell, enzymes digest them into their constituent amino acids, which then leave the cell across the basolateral membrane by transport proteins and are returned to the blood. Normally, this mechanism reabsorbs virtually all the proteins filtered, and hence the urine is essentially protein free. However, because the mechanism is easily saturated, an increase in filtered proteins causes proteinuria (appearance of protein in urine). Disruption of the glomerular filtration barrier to proteins increases the filtration of proteins and results in proteinuria. Proteinuria is frequently seen with kidney disease.

 

Secretion of Organic Anions and Organic Cations

 

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AT THE CELLULAR LEVEL

 

Water channels called aquaporins (AQPs) mediate the transcellular reabsorption of water across many nephron segments. In 2003, Dr. Peter Agre received the Nobel Prize in Chemistry for his discovery that AQPs regulate and facilitate water transport across cell membranes, a process essential to all living organisms. To date, 11 aquaporins have been identified. The AQP family is divided into two groups based on their permeability characteristics. One group (aquaporins) is permeable to water (AQP0, AQP1, AQP2, AQP4, AQP5, AQP6, and AQP8). The other group (aquaglyceroporins) is permeable to water and small solutes, especially glycerol (AQP3, AQP7, AQP9, AQP5, and AQP10). Aquaporins form tetramers in the plasma membrane of cells, with each subunit forming a water channel. In the kidneys, AQP1 is expressed in the apical and basolateral membranes of the proximal tubule and descending thin limb of Henle's loop. The importance of AQP1 in renal water reabsorption is underscored by studies in which AQP1 was "knocked out" in mice. These mice had increased urine output (polyuria) and a reduced ability to concentrate urine. In addition, the rate of water reabsorption by the proximal tubule was 50% less in mice lacking APQ1 than in normal mice. AQP7 and AQP8 are also expressed in the proximal tubule. AQP2 is expressed in the apical plasma membrane of principal cells in the collecting duct, and its expression in the membrane is regulated by antidiuretic hormone (ADH) (see Chapter 34). AQP3 and AQP4 are expressed in the basolateral membrane of principal cells in the collecting duct. Mice deficient in AQP3 or AQP4 (i.e., knockout mice) have defects in the ability to concentrate urine (see Chapter 34). AQPs are also expressed in many other organs in the body, including the lung, eye, skin, secretory glands, and brain, where they play key physiological roles. For example, AQP4 is expressed in cells that form the blood-brain barrier. Knockout of AQP4 in mice affects the water permeability of the blood-brain barrier such that brain edema is reduced in AQP4 knockout mice after acute water loading and hyponatremia.

 

 

AT THE CELLULAR LEVEL

 

Endocytosis of protein by the proximal tubule is mediated by apical membrane proteins that specifically bind luminal proteins and peptides. These peptides, called multiligand endocytic receptors, can bind a wide range of peptides and proteins and thereby mediate their endocytosis. Megalin and cubilin mediate protein and peptide endocytosis in the proximal tubule. Both are glycoproteins, with megalin being a member of the low-density lipoprotein receptor gene family.

 

 

Cells of the proximal tubule also secrete organic cations and organic anions. Secretion of organic cations and anions by the proximal tubule plays a key role in limiting the body's exposure to toxic compounds derived from endogenous and exogenous sources (i.e., xenobiotics). Many of the organic anions and cations (Tables 33-6 and 33-7) secreted by the proximal tubule are end products of metabolism that circulate in plasma. The proximal tubule also secretes numerous exogenous organic compounds, including numerous drugs and toxic chemicals. Many of these organic compounds can be bound to plasma proteins and are not readily filtered. Therefore, only a small proportion of these potentially toxic substances are eliminated from the body via excretion after filtration alone. Such substances are also secreted from the peritubular capillary into tubular fluid. These secretory mechanisms are very powerful and remove virtually all organic anions and cations from plasma that enter the kidneys. Hence, these substances are removed from plasma by both filtration and secretion.

 

 

 

Table 33-7. Some Organic Cations Secreted by the Proximal Tubule

 

Endogenous

Drugs

Creatinine
Dopamine
Epinephrine
Norepinephrine

Atropine
Isoproterenol
Cimetidine
Morphine
Quinine
Amiloride
Procainamide

 

 

 

IN THE CLINIC

 

Urinalysis is an important and routine tool for detection of disease. A thorough analysis of urine includes macroscopic and microscopic assessment. This is performed by visual assessment of the urine, microscopic examination, and chemical evaluation, which is conducted with dipstick reagent strips. The dipstick test is inexpensive and fast (i.e., less than 5 minutes). Dipstick reagent strips test urine for the presence of many substances, including bilirubin, blood, glucose, ketones, protein, and pH. It is normal to find trace amounts of protein in urine. Trace amounts of protein in urine can be derived from two sources: (1) filtration and incomplete reabsorption by the proximal tubule and (2) synthesis by the thick ascending limb of the loop of Henle. Cells in the thick ascending limb produce Tamm-Horsfall glycoprotein and secrete it into the tubular fluid. Because the mechanism for protein reabsorption is "upstream" of the thick ascending limb (i.e., proximal tubule), the secreted Tamm-Horsfall glycoprotein appears in urine. However, more than trace amounts of protein in urine are often indicative of renal disease.

 

 

Figure 33-5 illustrates the mechanisms of organic anion (OA-) transport across the proximal tubule. This secretory pathway has a maximum transport rate, low specificity (i.e., it transports many OA-s), and is responsible for secretion of all the OA-s listed in Table 33-6. OA-s are taken up into the cell, across the basolateral membrane, against their chemical gradient in exchange for α-ketoglutarate (α-KG) via several OA--α-KG antiporter mechanisms (OAT1, OAT2, and OAT3). α-KG accumulates inside the cells via metabolism of glutamate and by an Na+-α-KG symporter (i.e., a Na+-dicarboxylate transporter [NaDC]) also present in the basolateral membrane. Thus uptake of OA- into the cell against its electrochemical gradient is coupled to the exit of α-KG out of the cell, down its chemical gradient generated by the Na+-α-KG symporter mechanism. The resulting high intracellular concentration of OA- provides a driving force for exit of OA- across the luminal membrane into tubular fluid via a poorly understood mechanism. However, recent studies suggest that OA-s are transported across the apical membrane by OAT4, which is electrogenic, and by MRP2 (multidrug resistance-associated protein 2) (Fig. 33-5).

 

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IN THE CLINIC

 

Because organic anions compete for the same secretory pathways, elevated plasma levels of one anion often inhibit secretion of the others. For example, infusing p-aminohippuric acid (PAH) can reduce secretion of penicillin by the proximal tubule. Because the kidneys are responsible for eliminating penicillin, infusion of PAH into individuals who receive penicillin reduces penicillin excretion and thereby extends the biological half-life of the drug. In World War II, when penicillin was in short supply, hippurates were given with the penicillin to extend the drug's therapeutic effect.

 

The histamine H2 antagonist cimetidine is used to treat gastric ulcers. Organic cation transport mechanisms in the proximal tubule secrete cimetidine. If cimetidine is given to patients also receiving procainamide (a drug used to treat cardiac arrhythmias), cimetidine reduces the urinary excretion of procainamide (also an organic cation) by competing with this antiarrhythmic drug for the secretory pathway. Thus, coadministration of organic cations can increase the plasma concentration of both drugs to levels much higher than those seen when the drugs are given alone. This effect can lead to drug toxicity.

 

 

Figure 33-6 illustrates the mechanism of organic cation (OC+) transport across the proximal tubule. OC+s are taken up into the cell, across the basolateral membrane, by several transporters that have different substrate specificities. One mechanism that has not been completely characterized involves passive diffusion. In addition, OC+s are transported into proximal tubule cells across the basolateral membrane by three related transport proteins (OCT1, OCT2, and OCT3). These transporters mediate the diffusive uptake of OC+s into the cell. Uptake by all four mechanisms is driven by the magnitude of the cell's negative potential difference across the basolateral membrane. OC+ transport across the luminal membrane into tubular fluid, which is the rate-limiting step in secretion, is mediated by several transporters, including two OC+-H+ antiporters (OCTN1 and OCTN2) and MDR1 (a.k.a. P-glycoprotein). These transport mechanisms mediating secretion of OC+s are nonspecific; several OC+s usually compete for each transport pathway. Secretion of OC+s is stimulated by protein kinase A and C and by testosterone.

 

Henle's Loop

 

Henle's loop reabsorbs approximately 25% of the filtered NaCl and 15% of the filtered water. Reabsorption of NaCl in the loop of Henle occurs in both the thin ascending and thick ascending limbs. The descending thin limb does not reabsorb NaCl. Water reabsorption occurs exclusively in the descending thin limb via AQP1 water channels. The ascending limb is impermeable to water. In addition, Ca++ and HCO3- are also reabsorbed in the loop of Henle (see Chapters 35 and 36 for more details).

 

The thin ascending limb reabsorbs NaCl by a passive mechanism. Reabsorption of water, but not NaCl, in the descending thin limb increases [NaCl] in the tubule fluid entering the ascending thin limb. As the NaCl-rich fluid moves toward the cortex, NaCl diffuses out of the tubule fluid across the ascending thin limb into the medullary interstitial fluid, down a concentration gradient directed from the tubule fluid to the interstitium.

 

 

 

Figure 33-5 Secretion of organic anion (OA-) across the proximal tubule. OA-s enter the cell across the basolateral membrane by one of three OA--α-ketoglutarate (α-KG) antiporter mechanisms (OAT1, OAT2, OAT3). Uptake of α-KG into the cell, against its chemical concentration gradient, is driven by movement of Na+ into the cell via the Na+-dicarboxylate transporter (NaDC). The [Na+] inside the cell is low because of the Na+,K+-ATPase in the basolateral membrane, which transports Na+ out the cell in exchange for K+ (not shown). The α-KG recycles across the basolateral membrane on the OATs in exchange for OA-. OA-s leave the cell across the apical membrane, most likely by MRP2 and OAT4.

 

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Figure 33-6 Secretion of organic cation (OC+) across the proximal tubule. OC+s enter the cell across the basolateral membrane by four transport pathways: passive diffusion and three uniporters (OCT1, OCT2, OCT3, illustrated as one transporter for clarity) that mediate electrogenic uptake. Uptake of OC+s into the cell, against their chemical concentration gradient, is driven by the cell-negative potential difference. OC+s leave the cell across the apical membrane in exchange for H+ by two OC+-H+ antiporters (OCTN1, OCTN2, illustrated as one transporter for clarity) and MDR1.

 

 

 

Figure 33-7 Transport mechanisms for reabsorption of NaCl in the thick ascending limb of the loop of Henle. The positive charge in the lumen plays a major role in driving the passive paracellular reabsorption of cations. Mutations in the apical membrane K+ channel (ROMK), the apical membrane 1Na+-1K+-2Cl- symporter (NKCC2), or the basolateral Cl- channel (ClCNKB) cause Bartter's syndrome (see the clinical box on Bartter's syndrome). CA, carbonic anhydrase.

 

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The key element in the reabsorption of solute by the thick ascending limb is Na+,K+-ATPase in the basolateral membrane (Fig. 33-7). As with reabsorption in the proximal tubule, reabsorption of every solute by the thick ascending limb is linked to Na+,K+-ATPase. This pump maintains a low intracellular [Na+], which provides a favorable chemical gradient for the movement of Na+ from tubular fluid into the cell. Movement of Na+ across the apical membrane into the cell is mediated by the 1Na+-1K+-2Cl- symporter (NKCC2), which couples the movement of 1Na+ with 1K+ and 2Cl-. Using the potential energy released by the downhill movement of Na+ and Cl-, this symporter drives the uphill movement of K+ into the cell. The K+ channel in the apical plasma membrane plays an important role in reabsorption of NaCl by the thick ascending limb. This K+ channel allows the K+ transported into the cell via the 1Na+-1K+-2Cl- symporter to recycle back into tubule fluid. Because the [K+] in tubule fluid is relatively low, this K+ is required for continued operation of the 1Na+-1K+-2Cl- symporter. An Na+-H+ antiporter in the apical cell membrane also mediates Na+ reabsorption, as well as H+ secretion (HCO3- reabsorption), in the thick ascending limb (see also Chapter 36). Na+ leaves the cell across the basolateral membrane via Na+,K+-ATPase, whereas K+, Cl-, and HCO3- leave the cell across the basolateral membrane via separate pathways.

 

The voltage across the thick ascending limb is important for the reabsorption of several cations. The tubular fluid is positively charged relative to blood because of the unique location of transport proteins in the apical and basolateral membranes. Two points are important: (1) increased NaCl transport by the thick ascending limb increases the magnitude of the positive voltage in the lumen, and (2) this voltage is an important driving force for the reabsorption of several cations, including Na+, K+, Mg++, and Ca++, across the paracellular pathway (Fig. 33-7). The importance of the paracellular pathway to solute reabsorption is underscored by the observation that inactivating mutations of the tight junction protein claudin-16 reduce reabsorption of Mg++ and Ca++ by the ascending thick limb, even in the presence of positive transepithelial voltage in the lumen.

 

In summary, NaCl reabsorption across the thick ascending limb occurs via the transcellular and paracellular pathways. Fifty percent of NaCl reabsorption is transcellular, and 50% is paracellular. Because the thick ascending limb does not reabsorb water, reabsorption of NaCl and other solutes reduces the osmolality of tubular fluid to less than 150 mOsm/kg H2O. Thus, because the thick ascending limb produces a fluid that is dilute relative to plasma, the ascending limb of Henle's loop is called the "diluting segment."

 

Distal Tubule and Collecting Duct

 

AT THE CELLULAR LEVEL

 

As described in Chapter 1, epithelial cells are joined at their apical surfaces by tight junctions (a.k.a. zonula occludens). A number of proteins have now been identified as components of the tight junction, including proteins that span the membrane of one cell and link to the extracellular portion of the same molecule in the adjacent cell (e.g., occludin and claudins), as well as cytoplasmic linker proteins (e.g., ZO-1, ZO-2, and ZO-3) that link the membrane-spanning proteins to the cytoskeleton of the cell. Of these junctional proteins, claudins appear to be important in determining the permeability characteristics of the tight junction. As noted, claudin-16 is critical for the determining permeability of the tight junctions in the thick ascending limb of Henle's loop to divalent cations. Claudin-4 has been shown in cultured kidney cells to control the permeability of the tight junction to Na+, whereas claudin-15 determines whether a tight junction is permeable to cations or anions. Thus, the permeability characteristics of the tight junctions in different nephron segments are determined, at least in part, by the specific claudins expressed by the cells in that segment.

 

 

AT THE CELLULAR LEVEL

 

Bartter's syndrome is a set of autosomal recessive genetic diseases characterized by hypokalemia, metabolic alkalosis, and hyperaldosteronism (Table 33-3). Inactivating mutations in the gene coding for the 1Na+-1K+-2Cl- symporter (NKCC2 or SLC12A1), the apical K+ channel (KCNJ1 or ROMK), or the basolateral Cl-channel (ClCNKB) decrease both NaCl reabsorption and K+ reabsorption by the ascending thick limb, which in turn causes hypokalemia (i.e., low plasma [K+]) and a decrease in ECF volume. The fall in ECF volume stimulates aldosterone secretion, which in turn stimulates NaCl reabsorption and H+ secretion by the distal tubule and collecting duct (see later).

 

 

The distal tubule and collecting duct reabsorb approximately 8% of the filtered NaCl, secrete variable amounts of K+ and H+, and reabsorb a variable amount of water (≈8% to 17%). The initial segment of the distal tubule (early distal tubule) reabsorbs Na+, Cl-, and Ca++ and is impermeable to water (Fig. 33-8). Entry of NaCl into the cell across the apical membrane is mediated by an Na+-Cl- symporter (Fig. 33-8). Na+ leaves the cell via the action of Na+,K+-ATPase, and Cl- leaves the cell via diffusion through Cl- channels. Thus, dilution of tubular fluid begins in the thick ascending limb and continues in the early segment of the distal tubule.

 

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Figure 33-8 Transport mechanism for reabsorption of Na+ and Cl- in the early segment of the distal tubule. This segment is impermeable to water.

 

 

 

Figure 33-9 Transport pathways in principal cells and H+-secreting intercalated cells of the distal tubule and collecting duct. CA, carbonic anhydrase.

 

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The last segment of the distal tubule (late distal tubule) and the collecting duct are composed of two cell types: principal cells and intercalated cells. As illustrated in Figure 33-9, principal cells reabsorb NaCl and water and secrete K+. Intercalated cells secrete either H+ or HCO3- and are thus important in regulating acid-base balance (see Chapter 36). Intercalated cells also reabsorb K+ by the operation of an H+,K+-ATPase located in the apical plasma membrane. Both Na+ reabsorption and K+ secretion by principal cells depend on the activity of Na+,K+-ATPase in the basolateral membrane (Fig. 33-9). By maintaining a low intracellular [Na+], this pump provides a favorable chemical gradient for movement of Na+ from tubular fluid into the cell. Because Na+ enters the cell across the apical membrane via diffusion through epithelial Na+-selective channels (ENaCs) in the apical membrane, the negative charge inside the cell facilitates entry of Na+. Na+ leaves the cell across the basolateral membrane and enters the blood via the action of Na+,K+-ATPase. Reabsorption of Na+ generates a negative luminal voltage across the late distal tubule and collecting duct, which provides the driving force for reabsorption of Cl- across the paracellular pathway. A variable amount of water is reabsorbed across principal cells in the late distal tubule and collecting duct. Water reabsorption is mediated by the AQP2 water channel located in the apical plasma membrane and by AQP3 and AQP4 located in the basolateral membrane of principal cells. In the presence of antidiuretic hormone (ADH), water is reabsorbed. By contrast, in the absence of ADH, the distal tubule and collecting duct reabsorb little water (see Chapter 34).

 

K+ is secreted from blood into tubular fluid by principal cells in two steps (Fig. 33-9). First, uptake of K+ across the basolateral membrane is mediated by the action of Na+,K+-ATPase. Second, K+ leaves the cell via passive diffusion. Because [K+] inside the cells is high (≈150 mEq/L) and [K+] in tubular fluid is low (≈10 mEq/L), K+ diffuses down its concentration gradient through apical cell membrane K+ channels into tubular fluid. Although the negative potential inside the cells tends to retain K+ within the cell, the electrochemical gradient across the apical membrane favors secretion of K+ from the cell into tubular fluid (see Chapter 35). Reabsorption of K+ by intercalated cells is mediated by an H+,K+-ATPase located in the apical cell membrane.

 

REGULATION OF NaCl AND WATER REABSORPTION

 

Quantitatively, angiotensin II, aldosterone, catecholamines, natriuretic peptides, and uroguanylin are the most important hormones that regulate NaCl reabsorption and thereby urinary NaCl excretion (Table 33-8). However, other hormones (including dopamine and adrenomedullin), Starling forces, and the phenomenon of glomerulotubular balance influence NaCl reabsorption.

 

 

 

Table 33-8. Hormones That Regulate NaCl and Water Reabsorption

 

Hormone*

Major Stimulus

Nephron Site of Action

Effect on Transport

Angiotensin II

↑Renin

PT, TAL, DT/CD

↑NaCl and H2O reabsorption

Aldosterone

↑Angiotensin II, ↑[K+]p

TAL, DT/CD

↑NaCl and H2O reabsorption

ANP, BNP, urodilatin

↑ECFV

CD

↓H2O and NaCl reabsorption

Uroguanylin, guanylin

Oral ingestion of NaCl

PT, CD

↓H2O and NaCl reabsorption

Sympathetic nerves

↓ECFV

PT, TAL, DT/CD

↑NaCl and H2O reabsorption

Dopamine

↑ECFV

PT

↓H2O and NaCl reabsorption

ADH

↑Posm, ↓ECFV

DT/CD

↑H2O reabsorption

 

 


*All these hormones act within minutes, except aldosterone, which exerts its action on reabsorption of NaCl with a delay of 1 hour. Aldosterone achieves its maximal effect after a few days.
The effect on reabsorption of H2O does not include the thick ascending limb.
ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide, BP, blood pressure; CD, collecting duct; DT, distal tubule; ECFV, extracellular fluid volume; [K+]p, plasma K+ concentration; Posm, plasma osmolality; PT, proximal tubule; TAL, thick ascending limb.

 

ADH is the only major hormone that directly regulates the amount of water excreted by the kidneys.

 

Angiotensin II has a potent stimulatory effect on reabsorption of NaCl and water in the proximal tubule. It has also been shown to stimulate reabsorption of Na+ in the thick ascending limb of Henle's loop, as well as the distal tubule and collecting duct. A decrease in extracellular fluid (ECF) volume activates the reninangiotensin-aldosterone system (see Chapter 34 for more details), thereby increasing the plasma concentration of angiotensin II.

 

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Aldosterone is synthesized by the glomerulosa cells of the adrenal cortex, and it stimulates reabsorption of NaCl. It acts on the thick ascending limb of the loop of Henle, distal tubule, and collecting duct. Most of aldosterone's effect on NaCl reabsorption reflects its action on the distal tubule and collecting duct. Aldosterone also stimulates secretion of K+ by the distal tubule and collecting duct (see Chapter 35). Aldosterone increases the abundance of the Na+Cl- symporter in the early distal table. It enhances reabsorption of NaCl across principal cells in the distal tubule and collecting duct by four mechanisms: (1) increasing the amount of Na+,K+-ATPase in the basolateral membrane; (2) increasing expression of the sodium channel (ENaC) in the apical cell membrane; (3) elevating Sgk1 (serum glucocorticoid-stimulated kinase; see the Molecular Box) levels, which also increases the expression of ENaC in the apical cell membrane; and (4) stimulating CAP1 (channel-activating protease, also called "prostatin"), a serine protease that directly activates ENaCs by proteolysis. Taken together, these actions increase uptake of Na+ across the apical cell membrane and facilitate exit of Na+ from the cell interior into blood. The increase in reabsorption of Na+ generates negative transepithelial luminal voltage across the distal tubule and collecting duct. This negative voltage in the lumen provides the electrochemical driving force for reabsorption of Cl- across the tight junctions (i.e., paracellular pathway) in the distal tubule and collecting duct. Secretion of aldosterone is increased by hyperkalemia and angiotensin II (after activation of the reninangiotensin system) and decreased by hypokalemia and natriuretic peptides (see the following text). Through its stimulation of NaCl reabsorption in the collecting duct, aldosterone also indirectly increases water reabsorption by this nephron segment.

 

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) inhibit NaCl and water reabsorption. Secretion of ANP by the cardiac atria and BNP by the cardiac ventricles is stimulated by a rise in blood pressure and an increase in ECF volume. ANP and BNP reduce blood pressure by decreasing total peripheral resistance and enhancing urinary excretion of NaCl and water. These hormones also inhibit reabsorption of NaCl by the medullary portion of the collecting duct and inhibit ADH-stimulated water reabsorption across the collecting duct. Moreover, ANP and BNP also reduce the secretion of ADH from the posterior pituitary. These actions of ANP and BNP are mediated by the activation of membrane-bound guanylyl cyclase receptors, which increases intracellular levels of the second messenger cGMP. ANP induces a more profound natriuresis and diuresis than BNP does.

 

AT THE CELLULAR LEVEL

 

Sgk1 (serum glucocorticoid-stimulated kinase), a serine/threonine kinase, plays an important role in maintaining NaCl and K+ homeostasis by regulating excretion of NaCl and K+ by the kidneys. Studies in Sgk1 knockout mice reveal that this kinase is required for animals to survive severe NaCl restriction and K+ loading. NaCl restriction and K+ loading enhance plasma [aldosterone], which rapidly (in minutes) increases Sgk1 protein expression and phosphorylation. Phosphorylated Sgk1 enhances ENaC-mediated Na+ reabsorption in the collecting duct, primarily by increasing the number of ENaCs in the apical plasma membrane of principal cells and also by increasing the number of Na+,K+-ATPase pumps in the basolateral membrane. Phosphorylated Sgk1 inhibits Nedd4-2, a ubiquitin ligase that monoubiquitinylates ENaC subunits, thereby targeting them for endocytic removal from the plasma membrane and subsequent destruction in lysosomes. Inhibition of Nedd4-2 by Sgk1 reduces the monoubiquitinylation of ENaC, thereby reducing endocytosis and increasing the number of channels in the membrane. The mechanism whereby Sgk1 stimulates ROMK-mediated K+ excretion has not been elucidated. These effects of Sgk1 precede the aldosterone-stimulated increase in ENaC, ROMK, and Na+,K+-ATPase expression, which leads to a delayed (>4 hours), secondary increase in NaCl and K+ transport by the collecting duct. Activating polymorphisms in Sgk1 cause an increase in blood pressure, presumably by enhancing NaCl reabsorption by the collecting duct, which increases ECF volume and thereby blood pressure. As noted, CAP1 is a serine protease that directly activates ENaC by proteolysis of the channel proteins.

 

 

IN THE CLINIC

 

Liddle's syndrome is a rare genetic disorder characterized by an increase in blood pressure (i.e., hypertension) secondary to an increase in ECF volume. Liddle's syndrome is caused by activating mutations in either the β or γ subunit of the epithelial Na+ channel (ENaC, which is composed of three subunits, α, β, and γ). These mutations increase the number of Na+ channels in the apical cell membrane of principal cells and thereby the amount of Na+ reabsorbed by each channel. In Liddle's syndrome the rate of renal Na+ reabsorption is inappropriately high, which leads to an increase in ECF volume and hypertension.

 

There are two different forms of pseudohypoaldosteronism (PHA) (i.e., the kidneys reabsorb NaCl as they do when aldosterone levels are low; however, in PHA, aldosterone levels are elevated). The autosomal recessive form is caused by inactivating mutations in the α, β, or γ subunit of ENaC. The cause of the autosomal dominant form is an inactivating mutation in the mineralocorticoid receptor. PHA is characterized by an increase in Na+ excretion, a reduction in ECF volume, hyperkalemia, and hypotension.

 

 

IN THE CLINIC

 

Some individuals with expanded ECF volume and elevated blood pressure are treated with drugs that inhibit angiotensin-converting enzyme (ACE inhibitors [e.g., captopril, enalapril, lisinopril]) and thereby lower fluid volume and blood pressure. The inhibition of ACE blocks the degradation of angiotensin I to angiotensin II and thereby lowers plasma angiotensin II levels (see text for details). The decline in plasma angiotensin II concentration has three effects. First, reabsorption of NaCl and water by the nephron (especially the proximal tubule) falls. Second, aldosterone secretion decreases, thus reducing reabsorption of NaCl in the thick ascending limb, distal tubule, and collecting duct. Third, because angiotensin is a potent vasoconstrictor, a reduction in its concentration permits the systemic arterioles to dilate and thereby lower arterial blood pressure. ACE also degrades the vasodilator hormone bradykinin; ACE inhibitors therefore increase the concentration of bradykinin. Thus, ACE inhibitors decrease ECF volume and arterial blood pressure by promoting the renal excretion of NaCl and water and by reducing total peripheral resistance.

 

 

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Urodilatin and ANP are encoded by the same gene and have similar amino acid sequences. Urodilatin is a 32-amino acid hormone that differs from ANP by the addition of four amino acids to the amino-terminus. Urodilatin is secreted by the distal tubule and collecting duct and is not present in the systemic circulation; thus, urodilatin influences only the function of the kidneys. Secretion of urodilatin is stimulated by a rise in blood pressure and an increase in ECF volume. It inhibits NaCl and water reabsorption across the medullary portion of the collecting duct. Urodilatin is a more potent natriuretic and diuretic hormone than ANP is because some of the ANP that enters the kidneys in blood is degraded by a neutral endopeptidase that has no effect on urodilatin.

 

Uroguanylin and guanylin are produced by neuroendocrine cells in the intestine in response to the oral ingestion of NaCl. These hormones enter the circulation and inhibit NaCl and water reabsorption by the kidneys via the activation of membrane-bound guanylyl cyclase receptors, which increases intracellular [cGMP]. The natriuretic response of the kidneys to an NaCl load is more pronounced when given orally than when delivered intravenously because oral administration of NaCl causes the secretion of uroguanylin and guanylin.

 

Catecholamines stimulate reabsorption of NaCl. Catecholamines released from the sympathetic nerves (norepinephrine) and the adrenal medulla (epinephrine) stimulate reabsorption of NaCl and water by the proximal tubule, thick ascending limb of the loop of Henle, distal tubule, and collecting duct. Although sympathetic nerves are not active when ECF volume is normal, when ECF volume declines (e.g., after hemorrhage), sympathetic nerve activity rises and stimulates reabsorption of NaCl and water by these four nephron segments.

 

Dopamine, a catecholamine, is released from dopaminergic nerves in the kidneys and is also synthesized by cells of the proximal tubule. The action of dopamine is opposite that of norepinephrine and epinephrine. Secretion of dopamine is stimulated by an increase in ECF volume, and its secretion directly inhibits reabsorption of NaCl and water in the proximal tubule.

 

Adrenomedullin is a 52-amino acid peptide hormone that is produced by a variety of organs, including the kidneys. Adrenomedullin induces a marked diuresis and natriuresis, and its secretion is stimulated by congestive heart failure and hypertension. The major effect of adrenomedullin on the kidneys is to increase GFR and renal blood flow and thereby indirectly stimulate the excretion of NaCl and water.

 

ADH regulates water reabsorption. It is the most important hormone that regulates reabsorption of water in the kidneys (see Chapter 34). This hormone is secreted by the posterior pituitary gland in response to an increase in plasma osmolality (1% or more) or a decrease in ECF volume (>5% to 10% of normal). ADH increases the permeability of the collecting duct to water. It increases reabsorption of water by the collecting duct because of the osmotic gradient that exists across the wall of the collecting duct (see Chapter 34). ADH has little effect on urinary NaCl excretion.

 

 

 

Figure 33-10 Routes of solute and water transport across the proximal tubule and the Starling forces that modify reabsorption. (1) Solute and water are reabsorbed across the apical membrane. This solute and water then cross the lateral cell membrane. Some solute and water reenter the tubule fluid (3), and the remainder enters the interstitial space and then flows into the capillary (2). The width of the arrows is directly proportional to the amount of solute and water moving by pathways 1 to 3. Starling forces across the capillary wall determine the amount of fluid flowing through pathway 2 versus pathway 3. Transport mechanisms in the apical cell membranes determine the amount of solute and water entering the cell (pathway 1). Pi, interstitial hydrostatic pressure; Ppc, peritubular capillary hydrostatic pressure; πi, interstitial fluid oncotic pressure; πpc, peritubular capillary oncotic pressure. Thin arrows across the capillary wall indicate the direction of water movement in response to each force.

 

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Starling forces regulate reabsorption of NaCl and water across the proximal tubule. As previously described, Na+, Cl-, HCO3-, amino acids, glucose, and water are transported into the intercellular space of the proximal tubule. Starling forces between this space and the peritubular capillaries facilitate movement of the reabsorbed fluid into the capillaries. Starling forces across the wall of peritubular capillaries exert hydrostatic pressure in the peritubular capillary (Ppc) and lateral intercellular space (Pi) and oncotic pressure in the peritubular capillary (πpc) and lateral intercellular space (πi). Thus, reabsorption of water as a result of transport of Na+ from tubular fluid into the lateral intercellular space is modified by the Starling forces. Accordingly,


where J is flow (positive numbers indicate flow from the intercellular space into blood). Starling forces that favor movement from the interstitium into the peritubular capillaries are πpc and Pi (Fig. 33-10). The opposing Starling forces are πi and Ppc. Normally, the sum of the Starling forces favors the movement of solute and water from the interstitial space into the capillary. However, some of the solutes and fluid that enter the lateral intercellular space leak back into the proximal tubular fluid. Starling forces do not affect transport by the loop of Henle, distal tubule, and collecting duct because these segments are less permeable to water than the proximal tubule is.

 

A number of factors can alter the Starling forces across the peritubular capillaries surrounding the proximal tubule. For example, dilation of the efferent arteriole increases Ppc, whereas constriction of the efferent arteriole decreases it. An increase in Ppc inhibits solute and water reabsorption by increasing back-leak of NaCl and water across the tight junction, whereas a decrease stimulates reabsorption by decreasing back-leak across the tight junction.

 

Peritubular capillary oncotic pressure (πpc) is partially determined by the rate of formation of the glomerular ultrafiltrate. For example, if one assumes a constant plasma flow in the afferent arteriole, the plasma proteins become less concentrated in the plasma that enters the efferent arteriole and peritubular capillary as less ultrafiltrate is formed (i.e., as GFR decreases). Hence, πpc decreases. Thus πpc is directly related to the filtration fraction (FF = GFR/renal plasma flow [RPF]). A fall in the FF resulting from a decrease in GFR, at constant RPF, decreases πpc. This in turn increases the backflow of NaCl and water from the lateral intercellular space into tubular fluid and thereby decreases net reabsorption of solute and water across the proximal tubule. An increase in FF has the opposite effect.

 

The importance of Starling forces in regulating solute and water reabsorption by the proximal tubule is underscored by the phenomenon of glomerulotubular (G-T) balance. Spontaneous changes in GFR markedly alter the filtered load of Na+ (filtered load = GFR × [Na+] in the filtered fluid). Without rapid adjustments in Na+ reabsorption to counter the changes in filtration of Na+, urinary excretion of Na+ would fluctuate widely and disturb the Na+ balance of the body and thus alter ECF volume and blood pressure (see Chapter 34 for more details). However, spontaneous changes in GFR do not alter Na+ excretion in urine or Na+ balance because of the phenomenon of G-T balance. When body Na+ balance is normal (i.e., ECF volume is normal), G-T balance refers to the fact that reabsorption of Na+ and water increases in proportion to the increase in GFR and filtered load of Na+. Thus, a constant fraction of the filtered Na+ and water is reabsorbed from the proximal tubule despite variations in GFR. The net result of G-T balance is to reduce the impact of changes in GFR on the amount of Na+ and water excreted in urine.

 

Two mechanisms are responsible for G-T balance. One is related to the oncotic and hydrostatic pressure differences between the peritubular capillaries and the lateral intercellular space (i.e., Starling forces). For example, an increase in the GFR (at constant RPF) raises the protein concentration in glomerular capillary plasma above normal. This protein-rich plasma leaves the glomerular capillaries, flows through the efferent arterioles, and enters the peritubular capillaries. The increased πpc augments the movement of solute and fluid from the lateral intercellular space into the peritubular capillaries. This action increases net solute and water reabsorption by the proximal tubule.

 

The second mechanism responsible for G-T balance is initiated by an increase in the filtered load of glucose and amino acids. As discussed earlier, reabsorption of Na+ in the first half of the proximal tubule is coupled to that of glucose and amino acids. The rate of Na+ reabsorption therefore partially depends on the filtered load of glucose and amino acids. As the GFR and filtered load of glucose and amino acids increase, reabsorption of Na+ and water also rises.

 

In addition to G-T balance, another mechanism minimizes changes in the filtered load of Na+. As discussed in Chapter 32, an increase in the GFR (and thus in the amount of Na+ filtered by the glomerulus) activates the tubuloglomerular feedback mechanism. This action returns the GFR and filtration of Na+ to normal values. Thus, spontaneous changes in GFR (e.g., caused by changes in posture and blood pressure) increase the amount of Na+ filtered for only a few minutes. The mechanisms that underlie G-T balance maintain urinary Na+ excretion constant and thereby maintain Na+ homeostasis (and ECF volume and blood pressure) until the GFR returns to normal.

 

KEY CONCEPTS

 

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1.     The four major segments of the nephron (proximal tubule, Henle's loop, distal tubule, and collecting duct) determine the composition and volume of urine by the processes of selective reabsorption of solutes and water and secretion of solutes.

2.     Tubular reabsorption allows the kidneys to retain substances that are essential and regulate their levels in plasma by altering the degree to which they are reabsorbed. Reabsorption of Na+, Cl-, other anions, and organic anions and cations together with water constitutes the major function of the nephron. Approximately 25,200 mEq of Na+ and 179 L of water are reabsorbed each day. Proximal tubule cells reabsorb 67% of the glomerular ultrafiltrate, and cells of Henle's loop reabsorb about 25% of the NaCl that was filtered and about 15% of the water that was filtered. The distal segments of the nephron (distal tubule and collecting duct system) have a more limited reabsorptive capacity. However, final adjustments in the composition and volume of urine and most of the regulation by hormones and other factors occur in distal segments.

3.     Secretion of substances into tubular fluid is a means for excreting various byproducts of metabolism, and it also serves to eliminate exogenous organic anions and cations (e.g., drugs) and pollutants from the body. Many organic anions and cations are bound to plasma proteins and are therefore unavailable for ultrafiltration. Thus, secretion is their major route of excretion in urine.

4.     Various hormones (including angiotensin II, aldosterone, ADH, natriuretic peptides [ANP, BNP, and urodilatin], uroguanylin, and guanylin), sympathetic nerves, dopamine, and Starling forces regulate reabsorption of NaCl by the kidneys. ADH is the major hormone that regulates water reabsorption.



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