The reabsorption of NaCl in the thin ascending limb occurs through a passive mechanism. In the descending thin limb, only water is reabsorbed, leading to an increase in the concentration of NaCl in the tubule fluid entering the ascending thin limb. As the NaCl-rich fluid moves towards the cortex, NaCl diffuses out of the tubule lumen and into the medullary interstitial fluid, following a concentration gradient from the tubule fluid to the interstitium.

In the thick ascending limb, Na+,K+-ATPase in the basolateral membrane plays a key role in the reabsorption of solute. Similar to the proximal tubule, the reabsorption of every solute in the thick ascending limb is linked to the activity of Na+,K+-ATPase. This transporter maintains a low intracellular concentration of Na+, which creates a favorable chemical gradient for the movement of Na+ from the tubular fluid into the cell. The movement of Na+ across the apical membrane into the cell is facilitated by the 1Na+/1K+/2Cl− symporter (NKCC2), which transports 1Na+ with 1K+ and 2Cl− ions. The downhill movement of Na+ and Cl− provides the potential energy that drives the uphill movement of K+ into the cell. K+ channels in the apical plasma membrane (ROMK and Maxi-K) are important for the reabsorption of NaCl by the thick ascending limb. These K+ channels allow the K+ transported into the cell by the 1Na+/1K+/2Cl− symporter to recycle back into the tubule fluid. K+ recycling is necessary for the continued operation of the symporter as the concentration of K+ in the tubule fluid is relatively low. Additionally, a Na+/H+ antiporter (NHE3) in the apical cell membrane mediates the reabsorption of Na+ and the secretion of H+ (which is associated with HCO3− reabsorption) in the thick ascending limb. The operation of the Na+/H+ antiporter leads to the uptake of Na+ into the cell in exchange for H+. The production of H+ inside the cells generates HCO3−, which exits the cell across the basolateral membrane via a Cl−/HCO3− antiporter (AE2). Na+ leaves the cell through the basolateral membrane via the Na+,K+-ATPase, while K+ and Cl− leave the cell through separate pathways in the basolateral membrane (i.e., K+ and Cl− channels and the K+/Cl− symporter).

The early segment of the distal tubule, which is impermeable to water, reabsorbs NaCl through the NaCl symporter (NCC) located in the apical membrane. Mutations in this symporter can cause Gitelman syndrome.

The voltage across the thick ascending limb is crucial for the reabsorption of several cations. Due to the unique location of transport proteins in the apical and basolateral membranes, the tubular fluid is positively charged compared to blood. Two important points are: (1) increased NaCl transport by the thick ascending limb enhances the positive voltage in the lumen, and (2) this voltage serves as a driving force for the reabsorption of various cations, including Na+, K+, Mg++, and Ca++, through the paracellular pathway. The significance of the paracellular pathway in solute reabsorption is highlighted by the fact that inactivating mutations of the tight junction protein claudin-16 reduce the reabsorption of Mg++ and Ca++ by the thick ascending limb, even when there is a lumen positive transepithelial voltage.
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 lumen across the ascending thin limb and into the medullary interstitial fluid, down a concentration gradient directed from the tubule fluid to the interstitium (see for details).
The key element in reabsorption of solute by the thick ascending limb is Na+,K+-ATPase in the basolateral membrane (Fig. 34.7 ). As with reabsorption in the proximal tubule, reabsorption of every solute by the thick ascending limb is linked to Na+,K+-ATPase activity. This transporter maintains a low intracellular [Na+], which provides a favorable chemical gradient for the movement of Na+ from tubular fluid into the cell. This 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. K+ channels (ROMK and Maxi-K) in the apical plasma membrane play an important role in reabsorption of NaCl by the thick ascending limb. These K+ channels allow 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, K+ recycling is required for continued operation of the 1Na+/1K+/2Cl− symporter. A Na+/H+ anti-porter (NHE3) in the apical cell membrane also mediates Na+ reabsorption as well as H+ secretion (HCO3 − reabsorption) in the thick ascending limb (see also ). The operation of the Na+/H+ antiporter in the apical membrane results in cellular uptake of Na+ in exchange for H+ . The production of H+ inside cells generates HCO3 −, which exits the cell across the basolateral membrane via a Cl−/HCO3 − antiporter (AE2). Na+ leaves the cell across the basolateral membrane via the Na+,K+-ATPase, whereas K+ and Cl− leave the cell via separate pathways in the basolateral membrane (i.e., K+ and Cl− channels and the K+/Cl− symporter).
614 SECTION7Berne & Levy Physiology •Fig. 34.8 Transport mechanism for NaCl reabsorption in the early segment of the distal tubule. This segment is impermeable to water. Mutations in the apical membrane NaCl symporter (NCC) cause Gitelman syndrome. ATP H2O NCC Na+ K+ K+ K+ Na+ Cl– Blood Tubular fluid Cl–
The voltage across the thick ascending limb is important for 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 reabsorption of several cations, including Na+ , K+ , Mg++ , and Ca++ , across the paracellular pathway (see
Fig. 34.7 ). 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 a lumen positive transepithelial voltage.