Transport of Sodium and Chloride

The kidneys help to maintain the body's extracellular fluid (ECF) volume by regulating the amount of Na ⁺ in the urine. Sodium salts (predominantly NaCl) are the most important contributor to the osmolality of the ECF; hence, where Na ⁺ goes, water follows. This chapter focuses on how the kidneys maintain the ECF volume by regulating excretion of Na ⁺ and its most prevalent anion, Cl ⁻ .

The normal daily urinary excretion of Na ⁺ is only a tiny fraction of the total Na ⁺ filtered by the kidneys ( Fig. 35-1 ). The filtered load of Na ⁺ is the product of the glomerular filtration rate (GFR, ~180 L/day) and the plasma Na ⁺ concentration of ~142 mM (neglecting the small difference from [Na ⁺ ] in protein-free plasma water; see Table 5-2 ), or ~25,500 mmol/day. This amount is equivalent to the Na ⁺ in ~1.5 kg of table salt, more than nine times the total quantity of Na ⁺ present in the body fluids. For subjects on a typical Western diet containing ~120 mmol of Na ⁺ , the kidneys reabsorb ~99.6% of the filtered Na ⁺ by the time the tubule fluid reaches the renal pelvis. Therefore, even minute variations in the fractional reabsorptive rate can lead to changes in total-body Na ⁺ that markedly alter ECF volume and, hence, body weight and blood pressure. Thus, it is not surprising that each nephron segment makes its own unique contribution to Na ⁺ homeostasis.

Na ⁺ and Cl ⁻ Transport by Different Segments of The Nephron

Na ⁺ and Cl ⁻ reabsorption decreases from proximal tubules to Henle's loops to classic distal tubules to collecting tubules and ducts

Figure 35-2 summarizes the segmental distribution of Na ⁺ reabsorption along the nephron. The proximal tubule reabsorbs the largest fraction of filtered Na ⁺ (~67%). Because [Na ⁺ ] in tubule fluid (or TF _Na ; see p. 733 ) remains almost the same as that in plasma (i.e., TF _Na /P _Na = 1.0) throughout the length of the proximal tubule, it follows that the [Na ⁺ ] in the reabsorbate is virtually the same as that in plasma. Because Na ⁺ salts are the dominant osmotically active solutes in the filtrate, reabsorption must be a nearly isosmotic process. N35-1

$Figure 35-2, Estimates of renal handling of Na + along the nephron. The numbered yellow boxes indicate the absolute amount of Na + —as well as the fraction of the filtered load—that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen at these sites. The values in the boxes are approximations. P Na , plasma sodium concentration; U Na , urine sodium concentration; , urine flow.$

N35-1

The Proximal-Tubule Reabsorbate Is Slightly Hyperosmotic

Investigators have found that the lumen of the proximal tubule becomes slightly hypo -osmolar as the reabsorption of salt and water proceeds. Because the ultrafiltrate in Bowman's space is truly iso smotic with blood plasma, the reabsorbate (i.e., the fluid that the tubule reabsorbed) must be slightly hyper osmolar. Once the tubule has reabsorbed a slightly hyperosmolar solution, it has established an osmotic gradient along which water can flow by osmosis. The osmotic water permeability ( P _f ) of the proximal tubule is so high—owing to the extremely high expression of the water channel AQP1 in both the apical and basolateral membranes—that the H ₂ O very nearly keeps up, so to speak, with the solutes, in an osmotic sense. A mathematical way of stating this fact is that the ratio of the NaCl reabsorptive flux ( J _NaCl ) to the reabsorptive volume or H ₂ O flux ( J _V ) is nearly the same as the osmolality of the lumen:

\frac{J_{NaCl}}{J_{V}} = Osmolality of reabsorbate ≅ Osmolality of lumen

$\frac{J_{NaCl}}{J_{V}} = Osmolality of reabsorbate ≅ Osmolality of lumen$

In mice lacking AQP1, the water permeability of the proximal tubule is so low that the diffusion of H ₂ O can no longer keep up with the active reabsorption of NaCl, NaHCO ₃ , and other solutes. As a result, the reabsorbate can become markedly hyperosmolar, and the fluid left behind becomes markedly hypo-osmolar. This situation is reminiscent of that in the TAL, which is sometimes called the diluting segment.

References

Schnermann J, Chou CL, Ma T, et. al.: Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci U S A 1998; 95: pp. 9660-9664.
Vallon V, Verkman AS, Schnermann J: Luminal hypotonicity in proximal tubules of aquaporin-1-knockout mice. Am J Physiol Renal Physiol 2000; 278: pp. F1030-F1033.

The loop of Henle reabsorbs a smaller but significant fraction of filtered Na ⁺ (~25%). Because of the low water permeability of the thick ascending limb (TAL), this nephron segment reabsorbs Na ⁺ faster than it reabsorbs water, so that [Na ⁺ ] in the tubule fluid entering the distal convoluted tubule has decreased substantially (TF _Na /P _Na ≅ 0.45).

The classic distal tubule (see p. 729 ) and collecting ducts reabsorb smaller fractions of filtered Na ⁺ and water than do more proximal segments. The segments between the distal convoluted tubule (DCT) and the cortical collecting tubule (CCT), inclusive, reabsorb ~5% of the filtered Na ⁺ load under normal conditions. Finally, the medullary collecting duct reabsorbs ~3% of the filtered Na ⁺ load. Although the distal nephron reabsorbs only small amounts of Na ⁺ , it can establish a steep transepithelial concentration gradient and can respond to several hormones, including mineralocorticoids and arginine vasopressin (AVP).

As discussed on pages 763–769 , most nephron segments reabsorb greater amounts of Na ⁺ when increased quantities of Na ⁺ are delivered due to increased filtered load or inhibition of upstream Na ⁺ reabsorption.

The tubule reabsorbs Na ⁺ via both the transcellular and the paracellular pathways

The tubule can reabsorb Na ⁺ and Cl ⁻ via both transcellular and paracellular pathways ( Fig. 35-3 A ). In the transcellular pathway, Na ⁺ and Cl ⁻ sequentially traverse the apical and basolateral membranes before entering the blood. In the paracellular pathway, these ions move entirely by an extracellular route, through the tight junctions between cells. In the transcellular pathway, transport rates depend on the electrochemical gradients, ion channels, and transporters at the apical and basolateral membranes. However, in the paracellular pathway, transepithelial electrochemical driving forces and permeability properties of the tight junctions govern ion movements.

Figure 35-3, Transcellular and paracellular mechanisms of Na + and Cl − reabsorption. The example in B illustrates the electrochemical driving forces for Na + in the early proximal tubule. The equivalent circuit demonstrates that the flow of positive charge across the apical membrane slightly depolarizes the apical membrane (−67 mV) relative to the basolateral membrane (−70 mV).

Transcellular Na ⁺ Reabsorption

The basic mechanism of transcellular Na ⁺ reabsorption is similar in all nephron segments and is a variation on the classic two-membrane model of epithelial transport (see pp. 137–138 ). The first step is the passive entry of Na ⁺ into the cell across the apical membrane. Because the intracellular Na ⁺ concentration ([Na ⁺ ] _i ) is low and the cell voltage is negative with respect to the lumen, the electrochemical gradient is favorable for passive Na ⁺ entry across the apical membrane (see Fig. 35-3 B ). However, different tubule segments use different mechanisms of passive Na ⁺ entry across the apical membrane. The proximal tubule, the TAL, and the DCT all use a combination of Na ⁺ -coupled cotransporters and exchangers to move Na ⁺ across the apical membrane; however, in the cortical and medullary collecting ducts, Na ⁺ enters the cell through epithelial Na ⁺ channels (ENaCs).

The second step of transcellular Na ⁺ reabsorption is the active extrusion of Na ⁺ out of the cell across the basolateral membrane (see Fig. 35-3 B ). This Na ⁺ extrusion is mediated by the Na-K pump (see pp. 115–117 ), which keeps [Na ⁺ ] _i low (~15 mM) and [K ⁺ ] _i high (~120 mM). Because the basolateral membrane is primarily permeable to K ⁺ , it develops a voltage of ~70 mV, with the cell interior negative with respect to the interstitial space. Across the apical membrane, the cell is negative with respect to the lumen. The magnitude of the apical membrane voltage may be either lower or higher than that of the basolateral membrane, depending on the nephron segment and its transport activity.

Paracellular Na ⁺ Reabsorption

The basic mechanism of paracellular Na ⁺ transport is similar among nephron segments: the transepithelial electrochemical gradient for Na ⁺ drives transport. However, both the transepithelial voltage ( V _te ) and luminal [Na ⁺ ] vary along the nephron ( Table 35-1 ). As a result, the net driving force for Na ⁺ is positive—favoring passive Na ⁺ reabsorption—only in the S2 and S3 segments of the proximal tubule and in the TAL. In the other segments, the net driving force is negative—favoring passive Na ⁺ diffusion from blood to lumen (“backleak”). In addition to undergoing purely passive, paracellular reabsorption in the S2 and S3 segments and TAL, Na ⁺ can move uphill from lumen to blood via solvent drag across the tight junctions. In this case, the movement of H ₂ O from the lumen to the lateral intercellular space—energized by the active transport of Na ⁺ into the lateral intercellular space—also sweeps Na ⁺ and Cl ⁻ in the same direction.

TABLE 35-1

Transepithelial Driving Forces for Na ⁺

	LUMINAL [Na ⁺ ]	TRANSEPITHELIAL CHEMICAL DRIVING FORCE * ^†	TRANSEPITHELIAL VOLTAGE (ELECTRICAL DRIVING FORCE) ^† ^‡	TRANSEPITHELIAL ELECTROCHEMICAL DRIVING FORCE ^†
Proximal tubule, S1	142 mM	0 mV	−3 mV	−3 mV
Proximal tubule, S3	142 mM	0 mV	+3 mV	+3 mV
TAL	100 mM	−9 mV	+15 mV	+6 mV
DCT	70 mM	−19 mV	−5 to +5 mV	−24 to −14 mV
CCT	40 mM	−34 mV	−40 mV	−74 mV

* The chemical driving force is calculated assuming a plasma [Na ⁺ ] of 142 mM and is given in mV.

† A negative value promotes passive Na ⁺ movement from blood to lumen (i.e., backleak or secretion), whereas a positive value promotes passive Na ⁺ movement from lumen to blood (i.e., reabsorption).

‡ A negative value indicates that the lumen is negative with respect to the blood.

Nephron segments also vary in their leakiness to Na ⁺ ions. This leakiness is largely a function of the varying ionic conductance of the paracellular pathway between cells across the tight junction, due to the expression of different claudins. In general, the leakiness of the paracellular pathway decreases along the nephron from the proximal tubule (the most leaky) to the papillary collecting ducts. However, even the tightest renal epithelia have what might be regarded as only a moderate degree of tightness compared with truly “tight” epithelia, such as in those the skin, the gastric mucosa, and the urinary bladder (see pp. 136–137 ).

The leakiness of an epithelium has serious repercussions for the steepness of the ion gradients that the epithelium can develop and maintain. For both Na ⁺ and Cl ⁻ , the ability of specific nephron segments to establish large concentration gradients correlates with the degree of tightness, which limits the backflux of ions between cells. Thus, the luminal fluid attains much lower concentrations of Na ⁺ and Cl ⁻ in the distal nephron than it does in the proximal tubule.

An important consequence of a highly leaky paracellular pathway is that it provides a mechanism by which the basolateral membrane voltage can generate a current that flows through the tight junctions and charges up the apical membrane, and vice versa (see Fig. 35-3 B ). For example, hyperpolarization of the basolateral membrane leads to a hyperpolarization of the apical membrane. A consequence of this paracellular electrical coupling is that the apical membrane of a leaky epithelium, such as the proximal tubule, has a membrane voltage that is negative (−67 mV in Fig. 35-3 B ) and close to that of the basolateral membrane (−70 mV in Fig. 35-3 B ), whereas one would expect that, based on the complement of channels and ion gradients at the apical membrane, the apical membrane would have a far less negative voltage. A practical benefit of this crosstalk is that it helps couple the activity of the basolateral electrogenic Na-K pump to the passive entry of Na ⁺ across the apical membrane. If the Na-K pump rate increases, not only does [Na ⁺ ] _i decrease, enhancing the chemical Na ⁺ gradient across the apical membrane, but also the basolateral membrane hyperpolarizes (i.e., the cell becomes more negative with respect to the blood). Electrical coupling translates this basolateral hyperpolarization to a concomitant apical hyperpolarization, thus also enhancing the electrical gradient favoring apical Na ⁺ entry.

Na ⁺ and Cl ⁻ , and Water Transport at the Cellular and Molecular Level

Na ⁺ reabsorption involves apical transporters or ENaCs and a basolateral Na-K pump

Proximal Tubule

Along the first half of the tubule ( Fig. 35-4 A ), a variety of cotransporters in the apical membrane couples the downhill uptake of Na ⁺ to the uphill uptake of solutes such as glucose, amino acids, phosphate, sulfate, lactate, and citrate. Many of these Na ⁺ -driven cotransporters are electrogenic, carrying net positive charge into the cell. Thus, both the low [Na ⁺ ] _i and the negative apical membrane voltage fuel the secondary active uptake of these other solutes, which we discuss in Chapter 36 . In addition to being coupled to the cotransporters, Na ⁺ entry is also coupled to the extrusion of H ⁺ through the electroneutral Na-H exchanger 3 (NHE3). We discuss the role of NHE3 in renal acid secretion on page 827 .

Figure 35-4, Cell models of Na + reabsorption. PCT, proximal convoluted tube.

Both cotransporters and exchangers exploit the downhill Na ⁺ gradient across the apical cell membrane that is established by the Na-K pump in the basolateral membrane. The Na-K pump—and, to a lesser extent, the electrogenic Na/HCO ₃ cotransporter 1 (NBCe1) —are also responsible for the second step in Na ⁺ reabsorption, moving Na ⁺ from cell to blood. The presence of K ⁺ channels in the basolateral membrane is important for two reasons. First, these channels establish the negative voltage across the basolateral membrane and establish a similar negative voltage across the apical membrane via paracellular electrical coupling. Second, these channels permit the recycling of K ⁺ that had been transported into the cell by the Na-K pump.

Because of a lumen-negative V _te in the early proximal tubule, as well as a paracellular pathway that is permeable to Na ⁺ , approximately one third of the Na ⁺ that is transported from lumen to blood by the transcellular pathway diffuses back to the lumen by the paracellular pathway (“backleak”).

Thin Limbs of Henle's Loop

Na ⁺ transport by the thin descending and thin ascending limbs of Henle's loop is almost entirely passive and paracellular (see p. 811 ).

Thick Ascending Limb

Two major pathways contribute to Na ⁺ reabsorption in the TAL: transcellular and paracellular (see Fig. 35-4 B ). The transcellular pathway includes two major mechanisms for taking up Na ⁺ across the apical membrane. Na/K/Cl cotransporter 2 (NKCC2) couples the inward movement of 1 Na ⁺ , 1 K ⁺ , and 2 Cl ⁻ ions in an electroneutral process driven by the downhill concentration gradients of Na ⁺ and Cl ⁻ (see p. 122 ). The second entry pathway for Na ⁺ is an NHE3. As in the proximal tubule, the basolateral Na-K pump keeps [Na ⁺ ] _i low and moves Na ⁺ to the blood.

Two features of the apical step of Na ⁺ reabsorption in the TAL are noteworthy. First, the loop diuretics (e.g., furosemide and bumetanide) inhibit Na/K/Cl cotransport. Second, a large fraction of the K ⁺ that NKCC2 brings into the cell recycles to the lumen via apical K ⁺ channels. These channels are essential for replenishing luminal K ⁺ and thus for maintaining adequate Na/K/Cl cotransport.

A key aspect of the paracellular pathway for Na ⁺ reabsorption in the TAL is a lumen-positive V _te (see Fig. 35-4 B ). Nearly all other epithelia have a lumen-negative V _te because the apical membrane voltage is less negative than the basolateral membrane voltage (see Fig. 5-20 B ). The TAL is just the opposite. Its lumen-positive V _te develops because of a substantial difference in the ion permeabilities of the apical and basolateral membranes. The apical membrane is K ⁺ selective, so that the apical membrane potential depends mainly on the cell-to-lumen [K ⁺ ] gradient. In contrast, the TAL basolateral membrane is permeable to both K ⁺ and Cl ⁻ . Hence, the basolateral membrane potential lies between the equilibrium potentials of Cl ⁻ (approximately −50 mV) and K ⁺ (approximately −90 mV), so that it is less negative than if the basolateral membrane were permeable only to K ⁺ . Because the apical membrane potential is more negative than the basolateral membrane potential, the V _te is lumen positive. N37-9 Because the TAL has a low water permeability, removing luminal NaCl leaves the remaining tubule fluid hypo-osmotic. Hence, the TAL is sometimes referred to as the diluting segment.

The lumen-positive V _te provides the driving force for the diffusion of Na ⁺ across the tight junctions, accounting for approximately half of the Na ⁺ reabsorption by the TAL. The lumen-positive V _te also drives the passive reabsorption of K ⁺ (see p. 798 ), Ca ²⁺ (see p. 787 ), and Mg ²⁺ (see p. 791 ) via the paracellular pathway.

Distal Convoluted Tubule

Na ⁺ reabsorption in the DCT occurs almost exclusively by the transcellular route (see Fig. 35-4 C ). The apical step of Na ⁺ uptake is mediated by an electroneutral Na/Cl cotransporter ( NCC; see p. 123 ) that belongs to the same family as NKCC2 in the TAL. However, the NCC differs from NKCC2 in being independent of K ⁺ and highly sensitive to thiazide diuretics. Although the thiazides produce less diuresis than do the loop diuretics, the thiazides are nevertheless effective in removing excess Na ⁺ from the body. The basolateral step of Na ⁺ reabsorption, as in other cells, is mediated by the Na-K pump. Because the DCT, like the TAL, has a low water permeability, removing luminal NaCl leaves the remaining tubule fluid even more hypo-osmotic. Hence, the DCT is also part of the “diluting segment.”

Initial and Cortical Collecting Tubules

Na ⁺ reabsorption in the connecting tubule, initial collecting tubule (ICT), and CCT is transcellular and mediated by the majority cell type, the principal cell (see Fig. 35-4 D ). The neighboring β-intercalated cells are important for reabsorbing Cl ⁻ , as discussed below. Na ⁺ crosses the apical membrane of the principal cell via the epithelial Na ⁺ channel ( ENaC; see Table 6-2 , family No. 14), which is distinct from the voltage-gated Na ⁺ channels expressed by excitable tissues (see p. 187 ). ENaC is a trimer comprising homologous α, β, and γ subunits, each of which has two membrane-spanning segments. This channel is unique in that low levels of the diuretic drug amiloride specifically block it. This compound is a relatively mild diuretic because Na ⁺ reabsorption along the collecting duct is modest. N23-14 The basolateral step of Na ⁺ reabsorption is mediated by the Na-K pump, which also provides the electrochemical driving force for the apical entry of Na ⁺ .

The unique transport properties of the apical and basolateral membranes of the principal cells are also the basis for the lumen-negative V _te of approximately −40 mV in the CCT (see Table 35-1 ). In addition to ENaCs, the CCT has both apical and basolateral K ⁺ channels, which play a key role in K ⁺ transport (see p. 799 ). The apical entry of Na ⁺ (which tends to make the lumen negative) and the basolateral exit of K ⁺ (which tends to make the cell negative) are, in effect, two batteries of identical sign, arranged in series. In principle, these two batteries could add up to a V _te of ~100 mV (lumen negative). However, under most conditions, K ⁺ exit from cell to lumen partially opposes the lumen-negative potential generated by Na ⁺ entry. The net effect of these three batteries is a V _te of approximately −40 mV (lumen negative).

The V _te of the CCT can fluctuate considerably, particularly because of changes in the apical Na ⁺ battery owing to, for example, changes in luminal [Na ⁺ ]. In addition, changing levels of aldosterone or AVP may modulate the number of ENaCs that are open in the apical membrane and thus may affect the relative contribution of this Na ⁺ battery to apical membrane voltage.

Medullary Collecting Duct

The inner and outer medullary collecting ducts reabsorb only a minute amount of Na ⁺ , ~3% of the filtered load (see Fig. 35-2 ). It is likely that ENaC mediates the apical entry of Na ⁺ in these segments and that the Na-K pump extrudes Na ⁺ from the cell across the basolateral membrane (see Fig. 35-4 D ).

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Na + and Cl − Transport by Different Segments of The Nephron

Na + and Cl − reabsorption decreases from proximal tubules to Henle's loops to classic distal tubules to collecting tubules and ducts

References

The tubule reabsorbs Na + via both the transcellular and the paracellular pathways

Transcellular Na + Reabsorption

Paracellular Na + Reabsorption

Na + and Cl − , and Water Transport at the Cellular and Molecular Level

Na + reabsorption involves apical transporters or ENaCs and a basolateral Na-K pump