ePress. Published on May 1, 2014 as doi: 10.2215/CJN.08580813 Renal CJASN Physiology

Regulation of Potassium Homeostasis Biff F. Palmer

Abstract Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students. Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.08580813

Introduction Potassium plays a key role in maintaining cell function. Almost all cells possess an Na1-K1-ATPase, which pumps Na1 out of the cell and K1 into the cell and leads to a K1 gradient across the cell membrane (K1in. K1out) that is partially responsible for maintaining the potential difference across the membrane. This potential difference is critical to the function of cells, particularly in excitable tissues, such as nerve and muscle. The body has developed numerous mechanisms for defense of serum K 1 . These mechanisms serve to maintain a proper distribution of K1 within the body as well as regulate the total body K1 content.

Internal Balance of K1 The kidney is primarily responsible for maintaining total body K1 content by matching K1 intake with K1 excretion. Adjustments in renal K1 excretion occur over several hours; therefore, changes in extracellular K1 concentration are initially buffered by movement of K1 into or out of skeletal muscle. The regulation of K1 distribution between the intracellular and extracellular space is referred to as internal K1 balance. The most important factors regulating this movement under normal conditions are insulin and catecholamines (1). After a meal, the postprandial release of insulin functions to not only regulate the serum glucose concentration but also shift dietary K1 into cells until the kidney excretes the K1 load re-establishing K1 homeostasis. These effects are mediated through insulin binding to cell surface receptors, which stimulates glucose uptake in insulin-responsive tissues through the insertion of the glucose transporter protein GLUT4 (2,3). An increase in the activity of the Na1-K1-AT1 Pase mediates K uptake (Figure 1). In patients with the metabolic syndrome or CKD, insulin-mediated glucose uptake is impaired, but cellular K1 uptake remains normal (4,5), demonstrating differential regulation of insulin-mediated glucose and K1 uptake. www.cjasn.org Vol 0 ▪▪▪, 2015

Catecholamines regulate internal K1 distribution, with a-adrenergic receptors impairing and b-adrenergic receptors promoting cellular entry of K1. b2-Receptor–induced stimulation of K1 uptake is mediated by activation of the Na1-K1-ATPase pump. These effects play a role in regulating the cellular release of K1 during exercise (6). Under normal circumstances, exercise is associated with movement of intracellular K1 into the interstitial space in skeletal muscle. Increases in interstitial K1 can be as high as 10–12 mM with severe exercise. Accumulation of K1 is a factor limiting the excitability and contractile force of muscle accounting for the development of fatigue (7,8). Additionally, increases in interstitial K1 play a role in eliciting rapid vasodilation, allowing for blood flow to increase in exercising muscle (9). During exercise, release of catecholamines through b2 stimulation limits the rise in extracellular K1 concentration that otherwise occurs as a result of normal K1 release by contracting muscle. Although the mechanism is likely to be multifactorial, total body K1 depletion may blunt the accumulation of K1 into the interstitial space, limiting blood flow to skeletal muscle and accounting for the association of hypokalemia with rhabdomyolysis. Changes in plasma tonicity and acid–base disorders also influence internal K1 balance. Hyperglycemia leads to water movement from the intracellular to extracellular compartment. This water movement favors K1 efflux from the cell through the process of solvent drag. In addition, cell shrinkage causes intracellular K1 concentration to increase, creating a more favorable concentration gradient for K1 efflux. Mineral acidosis, but not organic acidosis, can be a cause of cell shift in K1. As recently reviewed, the general effect of acidemia to cause K1 loss from cells is not because of a direct K1-H1 exchange, but, rather, is because of an apparent coupling resulting from effects of acidosis on transporters that normally regulate cell pH in skeletal muscle (10) (Figure 2).

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Correspondence: Dr. Biff F. Palmer, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: biff.palmer@ utsouthwestern.edu

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Figure 1. | The cell model illustrates b2-adrenergic and insulinmediated regulatory pathways for K1 uptake. b2-Adrenergic and insulin both lead to K1 uptake by stimulating the activity of the Na1-K 1-ATPase pump primarily in skeletal muscle, but they do so through different signaling pathways. b2-Adrenergic stimulation leads to increased pump activity through a cAMP- and protein kinase A (PKA)–dependent pathway. Insulin binding to its receptor leads to phosphorylation of the insulin receptor substrate protein (IRS-1), which, in turn, binds to phosphatidylinositide 3-kinase (PI3-K). The IRS-1–PI3-K interaction leads to activation of 3-phosphoinositide–dependent protein kinase-1 (PDK1). The stimulatory effect of insulin on glucose uptake and K1 uptake diverge at this point. An Akt-dependent pathway is responsible for membrane insertion of the glucose transporter GLUT4, whereas activation of atypical protein kinase C (aPKC) leads to membrane insertion of the Na1-K1-ATPase pump (reviewed in ref. 3).

Intracellular K1 serves as a reservoir to limit the fall in extracellular K1 concentrations occurring under pathologic conditions where there is loss of K1 from the body. The efficiency of this effect was shown by military recruits undergoing training in the summer (11). These subjects were able to maintain a near-normal serum K1 concentration despite daily sweat K1 loses of .40 mmol and an 11day cumulative total body K1 deficit of approximately 400 mmol. Studies in rats using a K1 clamp technique afforded insight into the role of skeletal muscle in regulating extracellular K1 concentration (12). With this technique, insulin is administered at a constant rate, and K1 is simultaneously infused at a rate designed to prevent any drop in plasma K1 concentration. The amount of K1 administered is presumed to be equal to the amount of K1 entering the intracellular space of skeletal muscle. In rats deprived of K1 for 10 days, the plasma K1 concentration decreased from 4.2 to 2.9 mmol/L. Insulinmediated K1 disappearance declined by more than 90% compared with control values. This decrease in K1 uptake was accompanied by a .50% reduction in both the activity and expression of muscle Na1-K1-ATPase, suggesting that decreased pump activity might account for the decrease in insulin effect. This decrease in muscle K1 uptake, under conditions of K1 depletion, may limit excessive falls in extracellular K1 concentration that occur under conditions of insulin stimulation. Concurrently, reductions in pump

Figure 2. | The effect of metabolic acidosis on internal K1 balance in skeletal muscle. (A) In metabolic acidosis caused by inorganic anions (mineral acidosis), the decrease in extracellular pH will decrease the rate of Na1-H1 exchange (NHE1) and inhibit the inward rate of Na1 -3HCO3 cotransport (NBCe1 and NBCe2). The resultant fall in intracellular Na1 will reduce Na1-K1-ATPase activity, causing a net loss of cellular K1. In addition, the fall in extracellular HCO3 concentration will increase inward movement of Cl2 by Cl-HCO2 exchange, further enhancing K1 efflux by K1-Cl2 cotransport. (B) Loss of K1 from the cell is much smaller in magnitude in metabolic acidosis caused by an organic acidosis. In this setting, there is a strong inward flux of the organic anion and H1 through the monocarboxylate transporter (MCT; MCT1 and MCT4). Accumulation of the acid results in a larger fall in intracellular pH, thereby stimulating inward Na1 movement by way of Na1-H1 exchange and Na1-3HCO3 cotransport. Accumulation of intracellular Na1 maintains Na1-K1-ATPase activity, thereby minimizing any change in extracellular K1 concentration.

expression and activity facilitate the ability of skeletal muscle to buffer declines in extracellular K1 concentrations by donating some component of its intracellular stores. There are differences between skeletal and cardiac muscle in the response to chronic K1 depletion. Although skeletal muscle readily relinquishes K1 to minimize the drop in plasma K1 concentration, cardiac tissue K1 content remains relatively well preserved. In contrast to the decline in activity and expression of skeletal muscle Na 1 -K 1 -ATPase, cardiac Na 1 -K 1 -ATPase pool size

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increases in K1-deficient animals. This difference explains the greater total K1 clearance capacity after the acute administration of intravenous KCl to rats fed a K1-free diet for 2 weeks compared with K1-replete controls (13,14). Cardiac muscle accumulates a considerable amount of K1 in the setting of an acute load. When expressed on a weight basis, the cardiac capacity for K1 uptake is comparable with that of skeletal muscle under conditions of K1 depletion and may actually exceed skeletal muscle under control conditions.

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Potassium is freely filtered by the glomerulus. The bulk of filtered K1 is reabsorbed in the proximal tubule and loop of Henle, such that less than 10% of the filtered load reaches the distal nephron. In the proximal tubule, K1 absorption is primarily passive and proportional to Na1 and water (Figure 3). K1 reabsorption in the thick ascending limb of Henle occurs through both transcellular and paracellular pathways. The transcellular component is mediated by K1 transport on the apical membrane Na1-K1-2Cl2 cotransporter (Figure 4). K1 secretion begins in the early distal convoluted tubule and progressively increases along the distal nephron into the cortical collecting duct (Figure 5). Most urinary K1 can be accounted for by electrogenic K1 secretion mediated by principal cells in the initial collecting duct and the cortical collecting duct (Figure 6). An electroneutral K1 and Cl 2 cotransport mechanism is also present on the apical surface of the

distal nephron (15). Under conditions of K1 depletion, reabsorption of K1 occurs in the collecting duct. This process is mediated by upregulation in the apically located H1-K1 -ATPase on a-intercalated cells (16) (Figure 7). Under most homeostatic conditions, K1 delivery to the distal nephron remains small and is fairly constant. By contrast, the rate of K1 secretion by the distal nephron varies and is regulated according to physiologic needs. The cellular determinants of K1 secretion in the principal cell include the intracellular K1 concentration, the luminal K1 concentration, the potential (voltage) difference across the luminal membrane, and the permeability of the luminal membrane for K1. Conditions that increase cellular K1 concentration, decrease luminal K1 concentration, or render the lumen more electronegative will increase the rate of K1 secretion. Conditions that increase the permeability of the luminal membrane for K1 will increase the rate of K1 secretion. Two principal determinants of K1 secretion are mineralocorticoid activity and distal delivery of Na1 and water. Aldosterone is the major mineralocorticoid in humans and affects several of the cellular determinants discussed above, leading to stimulation of K1 secretion. First, aldosterone increases intracellular K1 concentration by stimulating the activity of the Na1-K1-ATPase in the basolateral membrane. Second, aldosterone stimulates Na1 reabsorption across the luminal membrane, which increases the electronegativity of the lumen, thereby increasing the electrical gradient favoring K1 secretion. Lastly, aldosterone has a direct effect on the luminal membrane to increase K1 permeability (17).

Figure 3. | A cell model for K1 transport in the proximal tubule. K1 reabsorption in the proximal tubule primarily occurs through the paracellular pathway. Active Na1 reabsorption drives net fluid reabsorption across the proximal tubule, which in turn, drives K1 reabsorption through a solvent drag mechanism. As fluid flows down the proximal tubule, the luminal voltage shifts from slightly negative to slightly positive. The shift in transepithelial voltage provides an additional driving force favoring K1 diffusion through the lowresistance paracellular pathway. Experimental studies suggest that there may be a small component of transcellular K1 transport; however, the significance of this pathway is not known. K1 uptake through the Na1-K1-ATPase pump can exit the basolateral membrane through a conductive pathway or coupled to Cl2. An apically located K1 channel functions to stabilize the cell negative potential, particularly in the setting of Na1-coupled cotransport of glucose and amino acids, which has a depolarizing effect on cell voltage.

Figure 4. | A cell model for K1 transport in the thick ascending limb of Henle. K1 reabsorption occurs by both paracellular and transcellular mechanisms. The basolateral Na1-K1-ATPase pump maintains intracellular Na1 low, thus providing a favorable gradient to drive the apically located Na1-K1-2Cl2 cotransporter (an example of secondary active transport). The apically located renal outer medullary K1 (ROMK) channel provides a pathway for K1 to recycle from cell to lumen, and ensures an adequate supply of K1 to sustain Na1-K1-2Cl2 cotransport. This movement through ROMK creates a lumen-positive voltage, providing a driving force for passive K1 reabsorption through the paracellular pathway. Some of the K1 entering the cell through the cotransporter exits the cell across the basolateral membrane, accounting for transcellular K1 reabsorption. K1 can exit the cell through a conductive pathway or in cotransport with Cl2. ClC-Kb is the primary pathway for Cl2 efflux across the basolateral membrane.

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Figure 5. | A cell model for K1 transport in the distal convoluted tubule (DCT). In the early DCT, luminal Na1 uptake is mediated by the apically located thiazide-sensitive Na1-Cl2 cotransporter. The transporter is energized by the basolateral Na1-K1-ATPase, which maintains intracellular Na1 concentration low, thus providing a favorable gradient for Na1 entry into the cell through secondary active transport. The cotransporter is abundantly expressed in the DCT1 but progressively declines along the DCT2. ROMK is expressed throughout the DCT and into the cortical collecting duct. Expression of the epithelial Na1 channel (ENaC), which mediates amiloridesensitive Na1 absorption, begins in the DCT2 and is robustly expressed throughout the downstream connecting tubule and cortical collecting duct. The DCT2 is the beginning of the aldosteronesensitive distal nephron (ASDN) as identified by the presence of both the mineralocorticoid receptor and the enzyme 11b-hydroxysteroid dehydrogenase II. This enzyme maintains the mineralocorticoid receptor free to only bind aldosterone by metabolizing cortisol to cortisone, the latter of which has no affinity for the receptor. Electrogenicmediated K1 transport begins in the DCT2 with the combined presence of ROMK, ENaC, and aldosterone sensitivity. Electroneutral K1-Cl2 cotransport is present in the DCT and collecting duct. Conditions that cause a low luminal Cl2 concentration increase K1 secretion through this mechanism, which occurs with delivery of poorly reabsorbable anions, such as sulfate, phosphate, or bicarbonate.

A second principal determinant affecting K1 secretion is the rate of distal delivery of Na1 and water. Increased distal delivery of Na1 stimulates distal Na1 absorption, which will make the luminal potential more negative and, thus, increase K1 secretion. Increased flow rates also increase K1 secretion. When K1 is secreted in the collecting duct, the luminal K1 concentration rises, which decreases the diffusion gradient and slows additional K1 secretion. At higher luminal flow rates, the same amount of K1 secretion will be diluted by the larger volume such that the rise in luminal K1 concentration will be less. Thus, increases in the distal delivery of Na1 and water stimulate K1 secretion by lowering luminal K1 concentration and making the luminal potential more negative.

Figure 6. | The cell that is responsible for K1 secretion in the initial collecting duct and the cortical collecting duct is the principal cell. This cell possesses a basolateral Na1-K1-ATPase that is responsible for the active transport of K1 from the blood into the cell. The resultant high cell K1 concentration provides a favorable diffusion gradient for movement of K1 from the cell into the lumen. In addition to establishing a high intracellular K1 concentration, activity of this pump lowers intracellular Na1 concentration, thus maintaining a favorable diffusion gradient for movement of Na1 from the lumen into the cell. Both the movements of Na1 and K1 across the apical membrane occur through well defined Na1 and K1 channels.

Figure 7. | Reabsorption of HCO3 in the distal nephron is mediated by apical H1 secretion by the a-intercalated cell. Two transporters secrete H1, a vacuolar H1-ATPase and an H1-K1-ATPase. The H1-K1 -ATPase uses the energy derived from ATP hydrolysis to secrete H1 into the lumen and reabsorb K1 in an electroneutral fashion. The activity of the H1-K1-ATPase increases in K1 depletion and, thus, provides a mechanism by which K1 depletion enhances both collecting duct H1 secretion and K1 absorption.

Two populations of K1 channels have been identified in the cells of the cortical collecting duct. The renal outer medullary K1 (ROMK) channel is considered to be the major K1-secretory pathway. This channel is characterized by having low conductance and a high probability of being open under physiologic conditions. The maxi-K1 channel (also known as the large-conductance K1 [BK] channel) is characterized by a large single channel conductance and quiescence in the basal state and activation under conditions of increased flow (18). In addition to increased delivery of Na1 and dilution of luminal K1 concentration, recruitment of maxi-K1 channels contributes to flow-dependent increased K1 secretion. Renal K1 channels are subjects of extensive reviews (19–21).

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The effect of increased tubular flow to activate maxi-K1 channels may be mediated by changes in intracellular Ca21 concentration (22). The channel is Ca21-activated, and an acute increase in flow increases intracellular Ca21 concentrations in the principal cell. It has been suggested that the central cilium (a structure present in principal cells) may facilitate transduction of signals of increased flow to increased intracellular Ca21 concentration. In cultured cells, bending of primary cilia results in a transient increase in intracellular Ca21, an effect blocked by antibodies to polycystin 2 (23). Although present in nearly all segments of the nephron, the maxi-K channel has been identified as the mediator of flow-induced K1 secretion in the distal nephron and cortical collecting duct (24). Development of hypokalemia in type II Bartter syndrome illustrates the importance of maxi-K1 channels in renal K1 excretion (25). Patients with type II Bartter syndrome have a loss-of-function mutation in ROMK manifesting with clinical features of the disease in the perinatal period. ROMK provides the pathway for recycling of K1 across the apical membrane in the thick ascending limb of Henle. This recycling generates a lumen-positive potential that drives the paracellular reabsorption of Ca21 and Mg21 and provides luminal K1 to the Na1-K1-2Cl2 cotransporter (Figure 4). Mutations in ROMK decrease NaCl and fluid reabsorption in the thick limb, mimicking a loop diuretic effect, which causes volume depletion. Despite the increase in distal Na1 delivery, K1 wasting is not consistently observed, because ROMK is also the major K1-secretory pathway for regulated K1 excretion in the collecting duct. In fact, in the perinatal period, infants with this form of Bartter syndrome often exhibit a transient hyperkalemia consistent with loss of function of ROMK in the collecting duct. However, over time, these patients develop hypokalemia as a result of increased flow-mediated K1 secretion through maxi-K1 channels. Studies in an ROMK-deficient mouse model of type II Bartter syndrome are consistent with this mechanism (26). The transient hyperkalemia observed in the perinatal period is likely related to the fact that ROMK channels are functionally expressed earlier than maxi-K1 channels during the course of development. In this regard, growing infants and children are in a state of positive K1 balance, which correlates with growth and increasing cell number. Early in development, there is a limited capacity of the distal nephron to secrete K1 because of a paucity of both apically located ROMK and maxi-K1 channels. The increase in K1-secretory capacity with maturation is initially a result of increased expression of ROMK. Several weeks later, maxi-K1 channel expression develops, allowing for flow-mediated K1 secretion to occur (reviewed in ref. 27). The limitation in distal K1 secretion is channelspecific, because the electrochemical gradient favoring K1 secretion, as determined by activity of the Na1-K1-ATPase and Na1 reabsorption, is not limiting. Additionally, increased flow rates are accompanied by appropriate increases in Na1 reabsorption and intracellular Ca21 concentrations in the distal nephron, despite the absence of stimulatory effect on K1 secretion (28). Activity of the H1- K1-ATPase, which couples K1 reabsorption to H1 secretion in intercalated cells, is similar in newborns and adults. K1 reabsorption through this pump, combined with decreased expression

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of K1-secretory channels, helps maintain a state of positive K1 balance during somatic growth after birth. These features of distal K1 handling by the developing kidney are a likely explanation for the high incidence of nonoliguric hyperkalemia in preterm infants (29). Another physiologic state characterized by a period of positive K1 balance is pregnancy, where approximately 300 mEq K1 is retained (30). High circulating levels of progesterone may play a role in this adaptation through stimulatory effects on K1 and H1 transport by the H1-K1 a2-ATPase isoform in the distal nephron (31). In addition to stimulating maxi-K1 channels, increased tubular flow has been shown to stimulate Na1 absorption through the epithelial Na1 channel (ENaC) in the collecting duct. This increase in absorption not only is because of increased delivery of Na1, but also seems to be the result of mechanosensitive properties intrinsic to the channel. Increased flow creates a shear stress that activates ENaCs by increasing channel open probability (32,33). It has been hypothesized that biomechanical regulation of renal tubular Na1 and K1 transport in the distal nephron may have evolved as a response to defend against sudden increases in extracellular K1 concentration that occur in response to ingestion of K1-rich diets typical of early vertebrates (22). According to this hypothesis, an increase in GFR after a protein-rich meal would lead to an increase in distal flow activating the ENaC, increasing intracellular Ca21 concentration, and activating maxi-K1 channels. These events would enhance K1 secretion, thus providing a buffer to guard against development of hyperkalemia. In patients with CKD, loss of nephron mass is counterbalanced by an adaptive increase in the secretory rate of K1 in remaining nephrons such that K1 homeostasis is generally well maintained until the GFR falls below 15–20 ml/ min (34). The nature of the adaptive process is thought to be similar to the adaptive process that occurs in response to high dietary K1 intake in normal subjects (35). Chronic K1 loading in animals augments the secretory capacity of the distal nephron, and, therefore, renal K1 excretion is significantly increased for any given plasma K1 level. Increased K1 secretion under these conditions occurs in association with structural changes characterized by cellular hypertrophy, increased mitochondrial density, and proliferation of the basolateral membrane in cells in the distal nephron and principal cells of the collecting duct. Increased serum K1 and mineralocorticoids independently initiate the amplification process, which is accompanied by an increase in Na1-K1-ATPase activity.

Aldosterone Paradox Under conditions of volume depletion, activation of the renin-angiotensin system leads to increased aldosterone release. The increase in circulating aldosterone stimulates renal Na1 retention, contributing to the restoration of extracellular fluid volume, but occurs without a demonstrable effect on renal K 1 secretion. Under condition of hyperkalemia, aldosterone release is mediated by a direct effect of K1 on cells in the zona glomerulosa. The subsequent increase in circulating aldosterone stimulates renal K1 secretion, restoring the serum K1 concentration to normal, but does so without concomitant renal Na1 retention.

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The ability of aldosterone to signal the kidney to stimulate salt retention without K1 secretion in volume depletion and stimulate K1 secretion without salt retention in hyperkalemia has been referred to as the aldosterone paradox (36). In part, this ability can be explained by the reciprocal relationship between urinary flow rates and distal Na1 delivery with circulating aldosterone levels. Under conditions of volume depletion, proximal salt and water absorption increase, resulting in decreased distal delivery of Na1 and water. Although aldosterone levels are increased, renal K1 excretion remains fairly constant, because the stimulatory effect of increased aldosterone is counterbalanced by the decreased delivery of filtrate to the distal nephron. Under condition of an expanded extracellular fluid volume, distal delivery of filtrate is increased as a result of decreased proximal tubular fluid reabsorption. Once again, renal K1 excretion remains relatively constant in this setting, because circulating aldosterone levels are suppressed. It is only under pathophysiologic conditions that increased distal Na1 and water delivery are coupled to increased aldosterone levels. Renal K1 wasting will occur in this setting (37) (Figure 8). Renal K1 secretion also remains stable during changes in flow rate resulting from variations in circulating vasopressin. In this regard, vasopressin has a stimulatory effect on renal K1 secretion (38,39). This kaliuretic property may serve to oppose a tendency to K1 retention under conditions of antidiuresis when a low-flow rate-dependent fall in distal tubular K1 secretion might otherwise occur. In contrast, suppressed endogenous vasopressin leads to decreased activity of the distal K1-secretory mechanism, thus limiting excessive K losses under conditions of full hydration and water diuresis. Although the inverse relationship between aldosterone levels and distal delivery of salt and water serves to keep renal K1 excretion independent of volume status, recent reviews have suggested a more complex mechanism centered on the with no lysine [K] 4 (WNK4) protein kinase in

the distal nephron (40,41). WNK4 is one of four members of a family of serine-threonine kinases each encoded by a different gene and characterized by the atypical placement of the catalytic lysine residue that is present in most other protein kinases. Inactivating mutations in WNK4 lead to development of pseudohypoaldosteronism type II (PHAII; Gordon syndrome). This disorder is inherited in an autosomal dominant fashion and is characterized by hypertension and hyperkalemia (42). Circulating aldosterone levels are low, despite the presence of hyperkalemia. Thiazide diuretics are particularly effective in treating both the hypertension and hyperkalemia (43). Wild-type WNK4 acts to reduce surface expression of the thiazide-sensitive Na1-Cl2 cotransporter and also stimulates clathrin-dependent endocytosis of ROMK in the collecting duct (44,45). The inactivating mutation of WNK4 responsible for PHAII leads to increased cotransporter activity and further stimulates endocytosis of ROMK. The net effect is increased NaCl reabsorption combined with decreased K1 secretion. Mutated WNK4 also enhances paracellular Cl2 permeability caused by increased phosphorylation of claudins, which are tight junction proteins involved in regulating paracellular ion transport (46). In addition to increasing Na1 retention, this change in permeability further impairs K1 secretion, because the lumennegative voltage, which normally serves as a driving force for K1 secretion, is dissipated. Because development of hypertension and hyperkalemia resulting from the PHAII-mutated WNK4 protein can be viewed as an exaggerated response to a reduction in extracellular fluid volume (salt retention without increased K1 secretion), it has been proposed that wild-type WNK4 may act as a molecular switch determining balance between renal NaCl reabsorption and K1 secretion (45,47). Under conditions of volume depletion, the switch would be altered in a manner reminiscent of the PHAII mutant such that NaCl reabsorption is increased, but K1 secretion is further

Figure 8. | Under normal circumstances, delivery of Na1 to the distal nephron is inversely associated with serum aldosterone levels. For this reason, renal K1 excretion is kept independent of changes in extracellular fluid volume. Hypokalemia caused by renal K1 wasting can be explained by pathophysiologic changes that lead to coupling of increased distal Na1 delivery and aldosterone or aldosterone-like effects. When approaching the hypokalemia caused by renal K1 wasting, one must determine whether the primary disorder is an increase in mineralocorticoid activity or an increase in distal Na1 delivery. EABV, effective arterial blood volume.

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inhibited. However, when increased serum K1 concentration occurs in the absence of volume depletion, WNK4 alterations result in maximal renal K1 secretion without Na1 retention. Angiotensin II (AII) has emerged as an important modulator of this switch. Under conditions of volume depletion, AII and aldosterone levels are increased (Figure 9). In addition to effects leading to enhanced NaCl reabsorption in the proximal tubule, AII activates the Na1-Cl2 cotransporter in a WNK4-dependent manner, and it is primarily located in the initial part of the distal convoluted tubule (DCT; DCT1) (48,49). AII also activates ENaC, which is found in the aldosterone-sensitive distal nephron (ASDN) comprised of the second segment of the DCT (DCT2), the connecting tubule, and the collecting duct (50). The activation of ENaC by AII is additive to that of aldosterone (51). In this manner, AII and aldosterone act in concert to stimulate Na1 retention. At the same time, AII inhibits ROMK by both WNK4-dependent and -independent mechanisms (52,53). This inhibitory effect on ROMK along with decreased Na1 delivery to the collecting duct brought about by AII stimulation of Na1 reabsorption in the proximal nephron, and DCT1 allows for simultaneous Na1 conservation without K1 wasting. Hyperkalemia, or an increase in dietary K1 intake, can increase renal K1 secretion independent of change in mineralocorticoid activity and without causing volume retention. This effect was shown in Wistar rats fed a diet very low in NaCl and K1 for several days and given a pharmacologic dose of deoxycorticosterone to ensure a constant and nonvariable effect of mineralocorticoids (54,55). After a KCl load administered into the peritoneal cavity, two distinct phases were noted. In the first 2 hours, there was a large increase in the rate of renal K1 excretion that

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was largely caused by an increase in the K1 concentration in the cortical collecting duct. During this early phase, flow through the collecting duct increased only slightly, suggesting that changes in K1 concentration were largely caused by an increase in K1-secretory capacity of the collecting duct. This effect would be consistent with known effects of dietary supplementation of K1 to increase channel density of both ROMK and maxi-K1 channels (56). In the subsequent 4 hours, renal K1 excretion continued to be high, but during this second phase, the kaliuresis was mostly accounted for by increased flow through the collecting duct. The increased flow was attributed to an inhibitory effect of increased interstitial K1 concentration on reabsorption of NaCl in the upstream ascending limb of Henle, an effect supported by microperfusion studies in the past (57,58). The timing of the two phases is presumably important, because higher flows would be most effective in promoting kaliuresis only after establishment of increased channel density. Although older studies are consistent with decreased Na1 absorption in the thick limb and proximal nephron after increased K1 intake, inhibitory effects in these high-capacity segments lack the precision and timing necessary to ensure that downstream delivery of Na1 is appropriate to maximally stimulate K1 secretion and at the same time, not be excessive, predisposing to volume depletion, particularly in the setting of a low Na1 diet (57–59). The low-capacity nature of the DCT and its location immediately upstream from the ASDN make this segment a more likely site for changes in dietary K1 intake to modulate Na1 transport and ensure that downstream delivery of Na1 is precisely the amount needed to ensure maintenance of K1 homeostasis without causing unwanted effects on volume.

Figure 9. | The aldosterone paradox refers to the ability of the kidney to stimulate NaCl retention with minimal K1 secretion under conditions of volume depletion and maximize K1 secretion without Na1 retention in hyperkalemia. With volume depletion (left panel), increased circulating angiotensin II (AII) levels stimulate the Na1-Cl2 cotransporter in the early DCT. In the ASDN, AII along with aldosterone stimulate the ENaC. In this latter segment, AII exerts an inhibitory effect on ROMK, thereby providing a mechanism to maximally conserve salt and minimize renal K1 secretion. When hyperkalemia or increased dietary K1 intake occurs with normovolemia (right panel), low circulating levels of AII or direct effects of K1 lead to inhibition of Na1-Cl2 cotransport activity along with increased activity of ROMK. As a result, Na1 delivery to the ENaC is optimized for the coupled electrogenic secretion of K1 through ROMK. As discussed in the text, with no lysine [K] 4 (WNK4) proteins are integrally involved in the signals by which the paradox is brought about. It should be emphasized the WNK proteins are part of a complex signaling network still being fully elucidated. The interested reader is referred to several recent reviews and advancements on this subject (48,51,91–93).

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In this regard, increased dietary K1 intake leads to an inhibitory effect on Na1 transport in this segment and does so through effects on WNK1, another member of the WNK family of kinases (60,61). WNK1 is ubiquitously expressed throughout the body in multiple spliced forms. By contrast, a shorter WNK1 transcript lacking the amino terminal 1–437 amino acids of the long transcript is highly expressed in the kidney but not other tissues, and it is referred to as kidney-specific WNK1 (KS-WNK1). KS-WNK1 is restricted to the DCT and part of the connecting duct and functions as a physiologic antagonist to the actions of long WNK1. Changes in the ratio of KS-WNK1 and long WNK1 in response to dietary K1 contribute to the physiologic regulation of renal K1 excretion (62–65). Under normal circumstances, long WNK1 prevents the ability of WNK4 to inhibit activity of the Na1-Cl2 cotransporter in the DCT. Thus, increased activity of long WNK1 leads to a net increase in NaCl reabsorption. Dietary K1 loading increases the abundance of KS-WNK1. Increased KS-WNK1 antagonizes the inhibitory effect of long WNK1 on WNK4. The net effect is inhibition of Na1-Cl2 cotransport in the DCT and increased Na1 delivery to more distal parts of the tubule. In addition, increased KS-WNK1 antagonizes the effect of long WNK1 to stimulate endocytosis of ROMK. Furthermore, KS-WNK1 exerts a stimulatory effect on the ENaC. Thus, increases in KS-WNK1 in response to dietary K 1 loading facilitate K 1 secretion through the combined effects of increased Na1 delivery through downregulation of Na1-Cl2 cotransport in the DCT, increased electrogenic Na1 reabsorption through the ENaC, and greater abundance of ROMK. Increased aldosterone levels in response to a high K1 diet lead to effects that complement the effects of KS-WNK1 (66,67). The serum- and glucocorticoid-dependent protein kinase (SGK1) is an immediate transcriptional target of aldosterone binding to the mineralocorticoid receptor. Activation of SGK1 leads to phosphorylation of WNK4, resulting in a loss of the ability of WNK4 to inhibit ROMK and the ENaC (66,68). Aldosterone-induced activation of SGK1 also leads to increased ENaC expression and activity by causing the phosphorylation of ubiquitin protein ligase Nedd4–2. Phosphorylated Nedd4–2 results in less retrieval of ENaC from the apical membrane (69). It should be emphasized that the absence of AII is a critical factor in the ability of high K1 intake to bring about the changes necessary to facilitate K1 secretion without excessive Na1 reabsorption.

Role in Hypertension Changes in KS-WNK1 and long WNK1 that occur in response to dietary K1 intake affect renal Na1 handling in a way that may be of importance in the observed relationship between dietary K1 intake and hypertension. Epidemiologic studies established that K1 intake is inversely related to the prevalence of hypertension (70). In addition, K1 supplements and avoidance of hypokalemia lowers BP in hypertensive subjects. By contrast, BP increases in hypertensive subjects placed on a low K1 diet. This increase in BP is associated with increased renal Na1 reabsorption (71). K 1 deficiency increases the ratio of long WNK1 to KS-WNK1. Long WNK1 is associated with increased retrieval

of ROMK, thus providing an appropriate response to limit K1 secretion. However, long WNK1 also leads to a stimulatory effect on ENaC activity as well as releasing the inhibitory effect of WNK4 on Na1 reabsorption mediated by the NaCl cotransporter in the DCT (72,73). These effects suggest that reductions in K1 secretion under conditions of K1 deficiency will occur at the expense of increased Na1 retention. Renal conservation of K1 and Na1 under conditions of K1 deficiency may be considered an evolutionary adaptation, because dietary K1 and Na1 deficiency likely occurred together for early humans (74). However, such an effect is potentially deleterious in our present setting, because evolution has seen a large increase in the ratio of dietary intake of Na1 versus K1. The effects of an increased ratio of WNK1 to KS-WNK1 in the kidney under conditions of modern day high Na1/low K1 diet could be central to the pathogenesis of salt-sensitive hypertension (75).

Enteric Sensor of K1 There is evidence to support the existence of enteric solute sensors capable of responding to dietary Na1, K1, and phosphate that signal the kidney to rapidly alter ion excretion or reabsorption (76–78). In experimental animals, and using protocols to maintain identical plasma K1 concentration, the kaliuretic response to a K1 load is greater when given as a meal compared with an intravenous infusion (79). These studies suggest that dietary K1 intake through a splanchnic sensing mechanism can signal increases in renal K1 excretion independent of changes in plasma K1 concentration or aldosterone (reviewed in ref. 80). Although the precise signaling mechanism is not known, recent studies suggest that the renal response may be because of rapid and nearly complete dephosphorylation of the Na1-Cl2 cotransporter in the DCT, causing decreased activity of the transporter and, thus, enhancing delivery of Na1 to the ASDN (81,82). In these studies, gastric delivery of K1 led to dephosphorylation of the cotransporter within minutes independent of aldosterone and based on in vitro studies, independent of changes in extracellular K1 concentration. The temporally associated increase in renal K1 excretion results from a more favorable electrochemical driving force caused by the downstream shift in Na1 reabsorption from the DCT to the ENaC in the ASDN as well as increased maxi-K1 channel K1 secretion brought on by increased flow. This rapid natriuretic response to increases in dietary K1 intake is consistent with the BP-lowering effect of K1-rich diets discussed earlier.

Circadian Rhythm of K1 Secretion

During a 24-hour period, urinary K1 excretion varies in response to changes in activity and fluctuations in K1 intake caused by the spacing of meals. However, even when K1 intake and activity are evenly spread over a 24-hour period, there remains a circadian rhythm whereby K1 excretion is lower at night and in the early morning hours and then increases in the afternoon (83–86). This circadian pattern results from changes in intratubular K1 concentration in the collecting duct as opposed to variations in urine flow rate (87). In the mouse distal nephron, a circadian rhythm exists for gene transcripts that encode proteins involving K1

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secretion (88). Gene expression of ROMK is greater during periods of activity, whereas expression of the H1-K1-ATPase is higher during rest, which correspond to periods when renal K1 excretion is greater and less, respectively (89). Changes in plasma aldosterone levels may play a contributory role, because circadian rhythm of glucocorticoid synthesis and secretion has been described in the adrenal gland. In addition, expression of clock genes within cells of the distal nephron suggests that a pacemaker function regulating K1 transport may be an intrinsic component of the kidney that is capable of operating independent of outside influence. The clinical significance of this rhythmicity in K1 and other electrolyte secretions is not known. Evidence suggests that dysregulation of circadian rhythms may contribute to a lack of nocturnal decline in BP, with eventual development of sustained hypertension as well as accelerated CKD and cardiovascular disease (85,90). Disclosures None. References 1. Palmer BF: A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis 56: 387–393, 2010 2. Foley K, Boguslavsky S, Klip A: Endocytosis, recycling, and regulated exocytosis of glucose transporter 4. Biochemistry 50: 3048–3061, 2011 3. Ho K: A critically swift response: Insulin-stimulated potassium and glucose transport in skeletal muscle. Clin J Am Soc Nephrol 6: 1513–1516, 2011 4. Nguyen TQ, Maalouf NM, Sakhaee K, Moe OW: Comparison of insulin action on glucose versus potassium uptake in humans. Clin J Am Soc Nephrol 6: 1533–1539, 2011 5. Alvestrand A, Wahren J, Smith D, DeFronzo RA: Insulin-mediated potassium uptake is normal in uremic and healthy subjects. Am J Physiol 246: E174–E180, 1984 6. Williams ME, Gervino EV, Rosa RM, Landsberg L, Young JB, Silva P, Epstein FH: Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 312: 823–827, 1985 7. Clausen T, Nielsen OB: Potassium, Na1,K1-pumps and fatigue in rat muscle. J Physiol 584: 295–304, 2007 8. McKenna MJ, Bangsbo J, Renaud JM: Muscle K1, Na1, and Cl disturbances and Na1-K1 pump inactivation: Implications for fatigue. J Appl Physiol (1985) 104: 288–295, 2008 9. Clifford PS: Skeletal muscle vasodilatation at the onset of exercise. J Physiol 583: 825–833, 2007 10. Aronson PS, Giebisch G: Effects of pH on potassium: New explanations for old observations. J Am Soc Nephrol 22: 1981– 1989, 2011 11. Knochel JP, Dotin LN, Hamburger RJ: Pathophysiology of intense physical conditioning in a hot climate. I. Mechanisms of potassium depletion. J Clin Invest 51: 242–255, 1972 12. McDonough AA, Youn JH: Role of muscle in regulating extracellular [K1]. Semin Nephrol 25: 335–342, 2005 13. Bundgaard H, Kjeldsen K: Potassium depletion increases potassium clearance capacity in skeletal muscles in vivo during acute repletion. Am J Physiol Cell Physiol 283: C1163–C1170, 2002 14. Bundgaard H: Potassium depletion improves myocardial potassium uptake in vivo. Am J Physiol Cell Physiol 287: C135–C141, 2004 15. Vela´zquez H, Ellison DH, Wright FS: Chloride-dependent potassium secretion in early and late renal distal tubules. Am J Physiol 253: F555–F562, 1987 16. DuBose TD Jr., Codina J, Burges A, Pressley TA: Regulation of H(1)-K(1)-ATPase expression in kidney. Am J Physiol 269: F500– F507, 1995 17. Stokes JB: Mineralocorticoid effect on K1 permeability of the rabbit cortical collecting tubule. Kidney Int 28: 640–645, 1985

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