Reabsorption of NaCl in the thick ascending limb occurs through transcellular and paracellular pathways. The transcellular pathway accounts for 50% of NaCl reabsorption, while the remaining 50% occurs via the paracellular pathway. Since the thick ascending limb lacks water channels (AQPs), it does not reabsorb water. As a result, the reabsorption of NaCl and other solutes reduces the osmolality of tubular fluid to less than 150 mOsm/kg H2O. Consequently, the segment consisting of the thick ascending limb of Henle's loop and the adjacent distal tubule is commonly referred to as the "diluting segments."

Moving on to the distal tubule and collecting duct, approximately 8% of filtered NaCl is reabsorbed, while variable amounts of K+ and H+ are secreted. Additionally, a variable amount of water (approximately 8%–17%) is reabsorbed. The early distal tubule reabsorbs Na+, Cl−, and Ca++ but is impermeable to water. The entry of NaCl into the cell across the apical membrane is facilitated by a Na+/Cl− symporter.

In Chapter 2, it is mentioned that epithelial cells in the distal tubule and collecting duct are connected by tight junctions (zonula occludens) at their apical surfaces. Various proteins have been identified as components of these tight junctions, including occludin, claudins, ZO-1, ZO-2, and ZO-3. Among these, claudins play a significant role in determining the permeability characteristics of tight junctions. For instance, claudin-16 and claudin-19 are critical determinants of divalent cation permeability in the thick ascending limb of Henle's loop. Mutations in claudin-16 and claudin-19 result in familial hypomagnesemia, hypercalciuria, and nephrocalcinosis. Claudin-2 is permeable to water and may contribute to paracellular water reabsorption in the proximal tubule. In cultured kidney cells, claudin-4 regulates the tight junction's permeability to Na+, while claudin-15 determines whether it is permeable to cations or anions. Therefore, the specific claudins expressed by cells in different segments of the nephron determine the permeability characteristics of their tight junctions.

In the presence of AVP (antidiuretic hormone), water reabsorption occurs in the late distal tubule and collecting duct. However, in the absence of AVP, minimal water reabsorption takes place.

Bartter syndrome is a group of autosomal recessive genetic disorders characterized by hypokalemia, metabolic alkalosis, and hyperaldosteronism. Inactivating mutations in the genes encoding the 1Na+/1K+/2Cl− symporter (NKCC2), the apical K+ channel (ROMK), or the basolateral Cl− channel (ClCNKB) lead to decreased reabsorption of both NaCl and K+ in the ascending thick limb. Consequently, hypokalemia and a decrease in extracellular fluid volume (ECFV) occur. The decrease in ECFV stimulates aldosterone secretion, which, in turn, promotes NaCl reabsorption and H+ secretion in the distal tubule and collecting duct.
In summary, NaCl reabsorption across the thick ascending limb occurs via transcellular and paracellular pathways. Fifty percent of NaCl reabsorption is transcellular, and 50% is paracellular. Because the thick ascending limb does not reabsorb water, owing to a lack of water channels (i.e., AQPs), 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 of Henle’s loop produces a fluid that is dilute relative to plasma, this segment and the adjacent distal tubule (as discussed next) are often collectively referred to as the “diluting segments.”
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%–17%). The initial segment of the distal tubule (early distal tubule) reabsorbs Na+, Cl−, and Ca++ and is impermeable to water (
Fig. 34.8 ). Entry of NaCl into the cell across the apical membrane is mediated by a Na+/Cl− symporter,
Chapter 2, epithelial cells are joined at their apical surfaces by tight junctions (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 major determinants of the permeability characteristics of tight junctions. For example, claudin-16 and claudin-19 are critical determinants of divalent cation permeability of the tight junctions in the thick ascending limb of Henle’s loop. Mutations in human claudin-16 and claudin19 cause familial hypomagnesemia (i.e., low plasma [Mg++]) with hypercalciuria (i.e., increased Ca++ in the urine) and nephrocalcinosis (i.e., calcification of the kidney). Claudin-2 is permeable to water and may be responsible for paracellular water reabsorption across the proximal tubule. 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.
AVP, water is reabsorbed. By contrast, in the absence of AVP the late distal tubule and collecting duct reabsorb little
Bartter syndrome is a set of autosomal recessive genetic diseases characterized by hypokalemia, metabolic alkalosis, and hyperaldosteronism (see
Table 34.3 ). Inactivating mutations in the gene coding for the 1Na+/1K+/2Cl− symporter (NKCC2), the apical K+ channel (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 ECFV. The fall in ECFV stimulates aldosterone secretion, which in turn stimulates NaCl reabsorption and H+ secretion by the distal tubule and collecting duct.