Passive K+ reabsorption along the proximal tubule follows Na+ and fluid movements
The proximal tubule reabsorbs most of the filtered K+, a process occurring via two paracellular mechanisms (Fig. 37-7A): electrodiffusion and solvent drag. The passive paracellular reabsorption of K+ by electrodiffusion (pp. 146–147) is very dependent on the luminal [K+] and transepithelial voltage (Vte). Water reabsorption tends to increase [K+] in the lumen, generating a favorable transepithelial gradient that drives passive absorption by diffusion across the paracellular pathway from lumen to blood. Moreover, as fluid flows down the proximal tubule, Vte shifts from lumen negative to lumen positive (see Table 35-1 and p. 759), which also favors K+ reabsorption by electrodiffusion via the low-resistance paracellular pathway.
FIGURE 37-7 Cellular models of K+ transport along the nephron.
In addition, some K+ may be reabsorbed by solvent drag (p. 467) across tight junctions. The greater the fluid reabsorption along the proximal tubule, the greater the reabsorption of K+ via both electrodiffusion and solvent drag. Indeed, one of the distinguishing features of proximal-tubule K+ reabsorption is its strong dependence on net fluid reabsorption. Thus, interventions that depress fluid reabsorption almost always inhibit K+ reabsorption.
Although the proximal tubule reabsorbs K+ via paracellular pathways, the proximal tubule has several cellular pathways for K+ movement that do not directly participate in K+ reabsorption (see Fig. 37-7A): (1) a basolateral Na-K pump, a feature common to all tubule cells; (2) apical and basolateral K+ channels; and (3) a basolateral K/Cl cotransporter (KCC).
The K+ conductance of the basolateral membrane greatly exceeds that of the apical membrane, and it appears that different channels are responsible for the K+ conductances in these two membranes. The open probability of the basolateral K+ channel increases sharply with the turnover rate of the Na-K pump. Accordingly, most of the K+ taken up via the Na-K pump recycles across the basolateral membrane via K+channels and a KCC, and does not appear in the lumen. This basolateral K+ channel belongs to the class of inwardly rectifying K+ channels—ROMK—characterized by ATP sensitivity: a decrease in [ATP]ienhances channel activity (p. 198). This regulation by [ATP]i is most likely involved in the coupling between basolateral Na-K pumps and K+ channels. An increase in pump rate—which could occur when increased apical Na+ entry increases [Na+]i—would lower [ATP]i, relieving inhibition of the K+ channels. Were it not for this crosstalk between the basolateral Na-K pump and apical K+ channels, the K+ content of proximal-tubule cells would fluctuate dramatically during alterations in net Na+ transport.
In contrast to the high state of activity of the basolateral K+ channels, apical K+ channels are largely quiescent under normal conditions. They appear to become active, however, when tubule cells swell, possibly when entry of Na+ from the lumen increases rapidly, such as by Na/glucose cotransport. These channels, which may respond to membrane stretch, then allow K+ to leave the cell, hyperpolarizing the apical membrane and thereby sustaining the driving force for inward Na/glucose cotransport. N37-4
Absence of Transcellular K+ Reabsorption in the Proximal Tubule
Contributed by Gerhard Giebisch, Erich Windhager, Peter Aronson
Even if the apical K+ channels were open more often, uptake of K+ across the apical membrane would not occur, because the electrochemical K+ gradient favors K+ movement from cell to lumen. Because K+cannot enter across the apical membrane, no transcellular reabsorption of K+ can take place. Thus, proximal-tubule K+ reabsorption must occur exclusively via the paracellular pathway.
K+ reabsorption along the TAL occurs predominantly via a transcellular route that exploits secondary active Na/K/Cl cotransport
As discussed on page 796, the tDLH of the loops of Henle, particularly those originating from juxtamedullary nephrons, secrete K+ (see Fig. 37-6). This secretion of K+ from the medullary interstitium into the tDLH lumen is passive, driven by the high [K+] of the medullary interstitium and made possible by a substantial K+ permeability. Both the tDLH lumen and the interstitium become increasingly K+ rich toward the tip of the papilla.
In the tALH, K+ moves from lumen to interstitium passively, via the paracellular pathway. The major driving force for this passive reabsorption of K+ is the lumen-to-interstitium K+ gradient, which becomes progressively larger as the fluid moves toward the cortex because interstitial [K+] becomes progressively lower toward the cortex.
The TAL of the loop of Henle reabsorbs K+ predominantly by a transcellular mechanism (see Fig. 37-7B). The lumen-positive Vte (pp. 757–758), N37-9 together with the relatively high paracellular K+permeability, could in principle allow passive K+ reabsorption to occur via the paracellular pathway. However, the high interstitial [K+] due to medullary K+ trapping opposes this process. Thus, it is uncertain how much K+ the TAL reabsorbs via the paracellular pathway.
Electrical Profile Across an Epithelial Cell in the TAL
Contributed by Emile Boulpaep, Walter Boron
Figure 5-20B shows the electrical profile typical of a cell from the renal proximal tubule. There, Vte (the transepithelial potential difference) is −3 mV with reference to the interstitial space because the membrane potential of −67 mV across the apical membrane (Va) is less negative than the membrane potential of −70 mV across the basolateral membrane (Vbl).
The situation in the TAL is a right-to-left mirror image of that in Figure 5-20B. A typical Vte in the TAL would be +15 mV (see Table 35-1) with reference to the interstitial space. The reason for this lumen-positive Vte is that the membrane potential across the apical membrane (e.g., −70 mV) is more negative than the membrane potential across the basolateral membrane (e.g., −55 mV).
Most of the K+ reabsorption by the TAL occurs via a transcellular pathway using the apical NKCC2 (p. 122). The major evidence for such a mechanism is the mutual interdependence of Na+, Cl−, and K+transport. Removing any of the three cotransported ions from the lumen abolishes transcellular K+ reabsorption. However, because inhibiting NKCC2 also abolishes the lumen-positive Vte (p. 757), this inhibition also blocks passive, paracellular K+ reabsorption.
The apical NKCC2 is a typical example of a secondary active transporter (p. 115). Expressed in electrical terms, the apical membrane potential is some 10 to 12 mV more positive than the K+ equilibrium potential, so that K+ would tend to diffuse passively from cell to lumen. Because the combined inward gradients of Na+ and Cl− across the apical membrane greatly exceed that of K+, the energy is adequate for the coupled uptake of all three ion species. Ultimately, a primary active transporter (i.e., Na-K pump) at the basolateral membrane drives the secondary active transport of K+ in the apical membrane. Inhibiting the basolateral Na-K pump leads to an increase in [Na+]i and [Cl−]i, so that apical Na/K/Cl transport ceases. A characteristic feature of NKCC2 is its sensitivity to a class of diuretics that have their main site of action in the TAL. Therefore, administering so-called loop diuretics such as furosemide or bumetanide blocks net reabsorption of Na+, Cl−, and K+.
The apical K+ conductance mentioned above—which mainly reflects ROMK (see Table 6-2, family No. 2) and BKCa (see Table 6-2, family No. 2)—is also important for the function of NKCC2 (see Fig. 37-7B). The major function of the apical K+ channel is to provide a mechanism for recycling much of the K+ from cell to lumen, so that luminal [K+] does not fall so low as to jeopardize Na/K/Cl cotransport (p. 757). Nevertheless, some of the K+ entering the cell via NKCC2 exits across the basolateral membrane, which accounts for transcellular K+ reabsorption. The presence of apical K+ channels also explains why inhibiting Na/K/Cl cotransport—either with loop diuretics (e.g., furosemide) or by deletion from the lumen of any of the cotransported ions—causes the TAL to engage in net K+ secretion. Active K+ uptake no longer opposes the K+ leak from the cell to lumen.
K+ secretion by principal and intercalated cells of the ICT and CCT involves active K+ uptake across the basolateral membrane
The early portion of the classic distal tubule (i.e., DCT) secretes K+ but at a relatively low rate. However, a high rate of K+ secretion into the tubule fluid is one of the distinguishing features of late portions of the classic distal tubule (i.e., CNT and ICT) and of the CCT. Of the two cell types in the ICT and CCT, it is the principal cell that is mainly responsible for secretion of K+, and it does so by a transcellular process (see Fig. 37-7C). The three key elements of the principal cell are (1) an Na-K pump for active K+ uptake at the basolateral membrane, (2) a relatively high (and variable) apical K+ permeability due to the ROMK channel, and (3) a favorable electrochemical driving force for K+ exit across the apical membrane. In addition, K+ may move from cell to lumen via an apical KCC (p. 123). The net effects are the active movement of K+ from blood to cell and the passive movement of K+ from cell to lumen. Changes in any of the three elements can affect the secretion of K+.
States of high luminal flow (e.g., osmotic diuresis, or administration of thiazide or loop diuretic drugs) increase K+ secretion via a transcellular mechanism involving α- and β-intercalated cells (p. 729) and principal cells. N37-5 Most of this flow-dependent K+ moves from cell to lumen via BKCa channels, which are more active when luminal flow increases. This flow dependence of K+ secretion helps explain the urinary K+ wasting that frequently occurs during states of high distal flow.
Basolateral K+ Uptake by Intercalated Cells
Contributed by Gerhard Giebisch, Peter Aronson
In intercalated cells, basolateral K+ uptake mainly takes place by Na/K/Cl cotransport. Because these cells have a very low activity of the Na-K pump, a K+-independent Na pump may be involved in maintaining the Na+ gradient needed to drive Na/K/Cl cotransport at the basolateral membrane.
Liu W, Schreck C, Coleman RA, et al. Role of NKCC in BK channel-mediated net K+ secretion in the CCD. Am J Physiol Renal Physiol. 2011;301:F1088–F1097.
K+ reabsorption by intercalated cells involves apical uptake via an H-K pump
Ultrastructurally, the ICT and CCT are nearly identical (p. 729); they are made up of ~70% principal cells (which secrete K+) and ~30% intercalated cells (some of which reabsorb K+).
As discussed above, the ICT, CCT, and MCD reabsorb K+ in response to K+ depletion (see Fig. 37-5A). This K+ reabsorption is transcellular (see Fig. 37-7D), mediated by both α- and β-intercalated cells in two steps: (1) an active step mediated by an apical ATP-driven H-K pump (pp. 117–118) similar to that present at the apical membrane of parietal cells in gastric glands (pp. 865–866), and (2) a passive step mediated by a basolateral K+ channel, which allows K+ to leak out. K+ depletion produces a marked increase in the abundance of H-K pumps, thereby enhancing K+ reabsorption. However, this increase in H-K pump activity tends to accelerate H+ secretion, which contributes to the development of hypokalemic alkalosis.
K+ reabsorption along the MCD is both passive and active
The capacity for K+ secretion diminishes from the cortical to the MCD. Indeed, the MCD is responsible for K+ reabsorption, which contributes to medullary K+ recycling (see Fig. 37-6). This K+ loss from the MCD lumen can occur by passive movement via the paracellular pathway—which has a significant K+ permeability—driven by a favorable K+ concentration gradient. The luminal [K+] of the MCD is high for two reasons. First, the segments just upstream (i.e., distal K+-secretory system) may have secreted K+. Second, the continuing reabsorption of fluid in the medullary collecting tubules, particularly in the presence of high arginine vasopressin (AVP) levels, further increases luminal [K+]. In addition to passive K+ reabsorption, apical H-K pumps (similar to those in intercalated cells, such as the α-intercalated cell in Fig. 37-7D) may mediate active K+ reabsorption, especially during low K+ intake.