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mOsmol/kg H2O

1200 mOsmol/kg H2O

FIGURE 2 Reabsorption of NaCl in the thin and thick ascending limb of the loop of Henle. At the papillary tip, approximately one-half of the interstitial osmolality of 1200 mOsm/kg H2O is due to 600 mmol/L urea, and half is due to 300 mmol/L NaCl (= 600 mOsm/kg H2O). In the thin ascending limb of the loop of Henle, NaCl is reabsorbed passively by diffusion down its concentration gradient from the lumen, where its concentration is ~575 mmol/L to the inner medullary interstitium. In the thick ascending limb, NaCl is actively reabsorbed, which further dilutes the tubular fluid. Because both the thin and thick segments of the ascending limb are virtually water impermeable, both mechanisms of NaCl reabsorption cause the osmolality of the luminal fluid to become less than that of the adjacent interstitium (shown by the lighter shading in the lumen).

thick ascending limb. This segment also serves to transport NaCl from the tubular lumen into the interstitial fluid without accompanying water movement. However, in this region, the transport of NaCl out of the lumen is an active, energy-requiring process, as shown in Fig. 3. Furthermore, the transporters that carry out this active NaCl reabsorption are unique. When isolated perfused segments of thick ascending limb were first examined in the early 1970s, it was recognized that, in contrast with most epithelia, these segments developed a lumen-positive voltage proportional to the rate of transport. They also actively reabsorbed Na+ and Cl" and reduced the NaCl concentration in the tubular fluid. This meant that Cl" was being transported against both a concentration gradient and an electrical potential difference (the positive luminal voltage). Initially, the process was referred to as active Cl" transport. Later investigation showed, however, that this transport process ultimately depended on energy from ATP hydrolysis by the Na+,K+-ATPase. The mechanisms involved are shown in Fig. 3.

NaCl

Urea

FIGURE 2 Reabsorption of NaCl in the thin and thick ascending limb of the loop of Henle. At the papillary tip, approximately one-half of the interstitial osmolality of 1200 mOsm/kg H2O is due to 600 mmol/L urea, and half is due to 300 mmol/L NaCl (= 600 mOsm/kg H2O). In the thin ascending limb of the loop of Henle, NaCl is reabsorbed passively by diffusion down its concentration gradient from the lumen, where its concentration is ~575 mmol/L to the inner medullary interstitium. In the thick ascending limb, NaCl is actively reabsorbed, which further dilutes the tubular fluid. Because both the thin and thick segments of the ascending limb are virtually water impermeable, both mechanisms of NaCl reabsorption cause the osmolality of the luminal fluid to become less than that of the adjacent interstitium (shown by the lighter shading in the lumen).

Tu bula Epithelial InlerstllEal

Lumen Cell Space

Tu bula Epithelial InlerstllEal

Lumen Cell Space

FIGURE 3 Active NaCl reabsorption in the thick ascending limb of the loop of Henle. The unique transporters in this nephron segment are highlighted in color. The movements of Na+, K+, and two Cl- ions across the luminal membrane are coupled by a furosemide-sensitive NaK2Cl cotransporter. Active Cl- accumulation in the cell is driven by the movement of Na+ down its concentration gradient, which is maintained by the basolateral Na+,K+-ATPase. K+ channels in the luminal membrane allow K+ accumulated in the cell by the cotransporter to recirculate, and they give rise to the lumen-positive voltage in this region of the nephron, which serves as a driving force for passive Na+ diffusion through the junctional complexes. Cl- leaves the cell primarily by Cl- channels in the basolateral membrane.

FIGURE 3 Active NaCl reabsorption in the thick ascending limb of the loop of Henle. The unique transporters in this nephron segment are highlighted in color. The movements of Na+, K+, and two Cl- ions across the luminal membrane are coupled by a furosemide-sensitive NaK2Cl cotransporter. Active Cl- accumulation in the cell is driven by the movement of Na+ down its concentration gradient, which is maintained by the basolateral Na+,K+-ATPase. K+ channels in the luminal membrane allow K+ accumulated in the cell by the cotransporter to recirculate, and they give rise to the lumen-positive voltage in this region of the nephron, which serves as a driving force for passive Na+ diffusion through the junctional complexes. Cl- leaves the cell primarily by Cl- channels in the basolateral membrane.

The unique characteristics of NaCl reabsorption by the thick ascending limb are imparted by the Na+/K+/2 Cl-cotransporter, which cotransports one Na+, one K+, and two Cl- ions. Thus, an electrically neutral combination of ions is transported into the cell from the tubular fluid. This is a ''downhill'' or passive transport process because of the favorable chemical potential gradients of Na+ and Cl-. (The electrical gradient is not of any consequence when one considers the movement of a neutral combination of ions coupled by a single transporter, as in this case.) Of course, energy is available for this process only as long as the cell maintains a low intracellular Na+ concentration. This ultimately depends on extrusion of Na+ from the cell across the basolateral membrane via the Na+,K+-ATPase. Because of the operation of the cotransporter, the Cl- concentration in the cell rises above its equilibrium value. Consequently, there is a favorable electrochemical potential difference across the basolat-eral membrane for Cl- diffusion out of the cell via Cl--selective channels, as shown in Fig. 3. K+ transported into the cell by the luminal cotransporter and by the

Na+,K+-ATPase leaves the cell by K+ channels in the luminal and basolateral membranes.

Another significant characteristic of the Na+/K+/ 2Cl- cotransporter in the thick ascending limb of the loop of Henle is its sensitivity to the most powerful diuretics. The class of diuretics that includes furosemide and bumetanide have a high affinity for the Cl- site on the cotransporter and block its operation. Because these diuretics are actively secreted into the proximal straight tubule, they have a much higher concentration in the lumen of the thick ascending limb than in the plasma. When the cotransporter is blocked, NaCl reabsorption by the thick ascending limb is greatly diminished, and increased loads of NaCl and isotonic fluid are delivered to the distal regions of the nephron. Because furosemide, bumetanide, and related drugs act on the medullary and cortical regions of the thick ascending limb, they are referred to as loop diuretics, and they interfere with the ability to concentrate or dilute the urine as will be discussed in Chapter 28.

The active NaCl reabsorptive mechanism described in Fig. 3 is present in both the medullary and cortical regions of the thick ascending limb and operates to dilute the tubular fluid in comparison with the medullary and cortical interstitium. However, the transporter is limited in its capacity to form a transepithelial NaCl gradient—as the NaCl concentration in the lumen falls, there is a gradient for diffusion of NaCl from the interstitium back into the tubular fluid. Thus, the medullary and cortical regions of the thick ascending limb can develop an NaCl gradient of approximately 75-100 mmol/L, resulting in a tubular fluid that is 150-200 mOsm/kg H2O dilute in comparison with the adjacent medullary interstitium, as shown in Fig. 4.

The rate of NaCl reabsorption by the thick ascending limb increases when the rate of NaCl delivery to the loop of Henle is increased by an increased GFR or by a decrease in proximal tubule reabsorption; however, this increase in reabsorption does not fully compensate for the increased delivery. Consequently, when more NaCl is delivered to the loop of Henle, although the rate of NaCl reabsorption by the thick ascending limb increases, less dilution of the tubular fluid osmolality occurs.

The rate of NaCl reabsorption in the thick ascending limb is also hormonally regulated. Vasopressin (also known as antidiuretic hormone or ADH) stimulates NaCl reabsorption in the medullary regions of the thick ascending limb and thus increases the transport of NaCl into the medullary interstitium and increases the interstitial fluid osmolality. (The regulation of vasopressin release and its role in the concentration and dilution of the urine are considered in Chapter 28.) In addition, increased osmolality of the medullary interstitium decreases NaCl reabsorption, as do locally produced

FIGURE 4 A reduction in tubular fluid osmolality is a consequence of NaCl absorption along the ascending limb of the loop of Henle. Because of passive NaCl reabsorption in the thin segment and active NaCl absorption in the thick segment (shown in Fig. 2), the osmolality of the tubular fluid falls to a steady-state value that is ~200 mOsm/kg H2O less than the adjacent interstitial fluid.

FIGURE 4 A reduction in tubular fluid osmolality is a consequence of NaCl absorption along the ascending limb of the loop of Henle. Because of passive NaCl reabsorption in the thin segment and active NaCl absorption in the thick segment (shown in Fig. 2), the osmolality of the tubular fluid falls to a steady-state value that is ~200 mOsm/kg H2O less than the adjacent interstitial fluid.

prostaglandins. This constitutes a negative feedback arc such that rising medullary osmolality counteracts excessive NaCl reabsorption via the thick ascending limb both by a direct effect on the thick ascending limb cells and by the production of prostaglandins.

As fluid leaves the medulla in the thick ascending limb, it is always hypotonic to plasma and to the adjacent interstitium, which is approximately isotonic to plasma. Thus, the tubular fluid that flows from the thick ascending limb to the distal convoluted tubule has an osmolality of 100-150 mOsm/kg H2O, with a urea concentration of 50 mmol/L or more. The collective rate of fluid delivery from the thick ascending limb to the distal convoluted tubule is ~15 mL/min, which is slightly more than 10% of the water volume filtered at the glomerulus (the GFR). The cortical region of the thick ascending limb is sometimes referred to as the diluting segment because it produces a tubular fluid that is dilute with respect to plasma, and this occurs regardless of the osmolality of the final urine.

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