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, P_i, 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.

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⁺-P_i, 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).

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, P_i, and lactate. Reabsorption of these solutes is mediated by the Na⁺–amino acid, Na⁺-P_i, and Na⁺-lactate symporters located in the apical membrane and the Na⁺,K⁺-ATPase, amino acid, P_i, 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.

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.

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.

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).

Table 33-4 NaCl Transport along the Nephron

Water Reabsorption

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.

Table 33-5 Water Transport along the Nephron

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.

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:

Equation 33-1

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

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 33-6 Some Organic Anions Secreted by the Proximal Tubule

Endogenous Anions

Drugs

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