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Renal Physiology

Renal Physiology

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

Regulation of

Biff F. Palmer

Abstract Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal of potassium under normal circumstances can provide a framework for approaching disorders of potassium Department of Internal Medicine, commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium University of Texas metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a Southwestern Medical resource for teaching trainees and medical students. Center, Dallas, Texas Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.08580813 Correspondence: Dr. Biff F. Palmer, Department of 1 Introduction regulate internal K distribution, with Internal Medicine, Potassium plays a key role in maintaining cell function. a-adrenergic receptors impairing and b-adrenergic recep- University of Texas 1 1 1 b – Southwestern Medical Almost all cells possess an Na -K -ATPase, which tors promoting cellular entry of K . 2-Receptor induced pumps Na1 out of the cell and K1 into the cell and 1 Center, 5323 Harry stimulation of K uptake is mediated by activation of the Hines Boulevard, 1 1 . 1 1 leads to a K gradient across the (K in Na -K -ATPase pump. These effects play a role in reg- Dallas, TX 75390. 1 1 K out) that is partially responsible for maintaining the ulating the cellular release of K during exercise (6). Email: biff.palmer@ potential difference across the membrane. This poten- Under normal circumstances, exercise is associated utsouthwestern.edu tial difference is critical to the function of cells, partic- with movement of intracellular K1 into the interstitial ularly in excitable tissues, such as nerve and muscle. space in skeletal muscle. Increases in interstitial K1 The body has developed numerous mechanisms for de- canbeashighas10–12 mM with severe exercise. 1 fense of serum K . These mechanisms serve to Accumulation of K1 is a factor limiting the excitabil- 1 maintain a proper distribution of K within the body ity and contractile force of muscle accounting for the 1 as well as regulate the total body K content. development of fatigue (7,8). Additionally, increases in interstitial K1 play a role in eliciting rapid vaso- fl Internal Balance of K1 dilation, allowing for ow to increase in exer- The is primarily responsible for maintaining cising muscle (9). During exercise, release of b total body K1 contentbymatchingK1 intake with K1 catecholamines through 2 stimulation limits the 1 rise in extracellular K1 concentration that otherwise excretion. Adjustments in renal K excretion occur 1 over several hours; therefore, changes in extracellular occurs as a result of normal K release by contracting K1 concentration are initially buffered by movement muscle. Although the mechanism is likely to be mul- 1 tifactorial, total body K1 depletion may blunt the ac- of K into or out of skeletal muscle. The regulation of 1 K1 distribution between the intracellular and extracel- cumulation of K into the interstitial space, limiting fl lular space is referred to as internal K1 balance. The blood ow to skeletal muscle and accounting for the most important factors regulating this movement under association of hypokalemia with rhabdomyolysis. – normal conditions are and catecholamines (1). Changes in plasma tonicity and acid base disorders fl 1 After a meal, the postprandial release of insulin also in uence internal K balance. Hyperglycemia functions to not only regulate the serum leads to movement from the intracellular to concentration but also shift dietary K1 into cells until extracellular compartment. This water movement fa- 1 1 1 fl the kidney excretes the K load re-establishing K ho- vors K ef ux from the cell through the process of meostasis. These effects are mediated through insulin . In addition, cell shrinkage causes intra- 1 binding to cell surface receptors, which stimulates glu- cellular K concentration to increase, creating a more 1 cose uptake in insulin-responsive tissues through the favorable concentration gradient for K efflux. Min- insertion of the protein GLUT4 eral acidosis, but not organic acidosis, can be a cause 1 1 1 (2,3). An increase in the activity of the Na -K -AT- of cell shift in K . As recently reviewed, the general 1 1 Pase mediates K uptake (Figure 1). In patients with effect of acidemia to cause K loss from cells is not the metabolic syndrome or CKD, insulin-mediated glu- because of a direct K1-H1 exchange, but, rather, is cose uptake is impaired, but cellular K1 uptake re- because of an apparent coupling resulting from ef- mains normal (4,5), demonstrating differential fects of acidosis on transporters that normally regu- regulation of insulin-mediated glucose and K1 uptake. late cell pH in skeletal muscle (10) (Figure 2). www.cjasn.org Vol 0 ▪▪▪,2015 Copyright © 2014 by the American Society of 1 2 Clinical Journal of the American Society of Nephrology

b Figure 1. | The cell model illustrates 2-adrenergic and insulin- 1 b mediated regulatory pathways for K uptake. 2-Adrenergic and insulinbothleadtoK1 uptake by stimulating the activity of the Na1-K1-ATPase pump primarily in skeletal muscle, but they do so b through different signaling pathways. 2-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 pro- tein (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).

1 1 Intracellular K serves as a reservoir to limit the fall in Figure 2. | The effect of on internal K balance in 1 extracellular K concentrations occurring under patho- skeletal muscle. (A) In metabolic acidosis caused by inorganic anions 1 logic conditions where there is loss of K from the body. (mineral acidosis), the decrease in extracellular pH will decrease the 1 1 1 The efficiency of this effect was shown by military recruits rate of Na -H exchange (NHE1) and inhibit the inward rate of Na -3HCO3 cotransport (NBCe1 and NBCe2). The resultant fall in in- undergoing training in the summer (11). These subjects 1 1 1 1 tracellular Na will reduce Na -K -ATPase activity, causing a net were able to maintain a near-normal serum K concentra- 1 1 . loss of cellular K . In addition, the fall in extracellular HCO3 concen- tion despite daily sweat K loses of 40 mmol and an 11- 2 2 1 tration will increase inward movement of Cl by Cl-HCO exchange, day cumulative total body K deficit of approximately 400 1 1 2 1 further enhancing K effluxbyK -Cl cotransport. (B) Loss of K from mmol. 1 the cell is much smaller in magnitude in metabolic acidosis caused byan Studies in rats using a K clamp technique afforded in- organic acidosis. In this setting, there is a strong inward flux of the or- 1 sight into the role of skeletal muscle in regulating extracel- ganic anion and H through the monocarboxylate transporter (MCT; 1 lular K concentration (12). With this technique, insulin is MCT1 and MCT4). Accumulation of the acid results in a larger fall in 1 1 administered at a constant rate, and K is simultaneously intracellular pH, thereby stimulating inward Na movement by way of 1 1 1 infused at a rate designed to prevent any drop in plasma Na -H exchange and Na -3HCO3 cotransport. Accumulation of in- 1 1 1 1 1 tracellular Na maintains Na -K -ATPase activity, thereby mini- K concentration. The amount of K administered is pre- 1 sumed to be equal to the amount of K1 entering the in- mizing any change in extracellular K concentration. tracellular space of skeletal muscle. In rats deprived of K1 for 10 days, the plasma K1 con- centration decreased from 4.2 to 2.9 mmol/L. Insulin- expression and activity facilitate the ability of skeletal muscle mediated K1 disappearance declined by more than 90% to buffer declines in extracellular K1 concentrations by do- compared with control values. This decrease in K1 uptake nating some component of its intracellular stores. was accompanied by a .50% reduction in both the activity There are differences between skeletal and cardiac and expression of muscle Na1-K1-ATPase, suggesting that muscle in the response to chronic K1 depletion. Although decreased pump activity might account for the decrease in skeletal muscle readily relinquishes K1 to minimize the insulin effect. This decrease in muscle K1 uptake, under drop in plasma K1 concentration, cardiac tissue K1 con- conditions of K1 depletion, may limit excessive falls in ex- tent remains relatively well preserved. In contrast to tracellular K1 concentration that occur under conditions of the decline in activity and expression of skeletal muscle insulin stimulation. Concurrently, reductions in pump Na1 -K1 -ATPase, cardiac Na1 -K1 -ATPase pool size Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 3

increases in K1-deficient animals. This difference explains distal (15). Under conditions of K1 depletion, re- the greater total K1 clearance capacity after the acute ad- absorption of K1 occurs in the collecting duct. This process ministration of intravenous KCl to rats fed a K1-free diet is mediated by upregulation in the apically located H1-K1 for 2 weeks compared with K1-replete controls (13,14). -ATPase on a-intercalated cells (16) (Figure 7). Cardiac muscle accumulates a considerable amount of Under most homeostatic conditions, K1 delivery to the 1 K in the setting of an acute load. When expressed on a distal nephron remains small and is fairly constant. By con- 1 weight basis, the cardiac capacity for K uptake is compa- trast, the rate of K1 secretion by the distal nephron varies 1 rable with that of skeletal muscle under conditions of K and is regulated according to physiologic needs. The cellular depletion and may actually exceed skeletal muscle under determinants of K1 secretion in the principal cell include the control conditions. intracellular K1 concentration, the luminal K1 concentration, the potential (voltage) difference across the luminal mem- brane, and the permeability of the luminal membrane for Renal Potassium Handling K1. Conditions that increase cellular K1 concentration, de- Potassium is freely filtered by the . The bulk crease luminal K1 concentration, or render the lumen more 1 of filtered K is reabsorbed in the and electronegative will increase the rate of K1 secretion. Con- , such that less than 10% of the filtered ditions that increase the permeability of the luminal mem- load reaches the distal nephron. In the proximal tubule, brane for K1 will increase the rate of K1 secretion. Two 1 K absorption is primarily passive and proportional to principal determinants of K1 secretion are mineralocorticoid 1 1 Na and water (Figure 3). K in the thick activity and distal delivery of Na1 and water. ascending limb of Henle occurs through both transcellular is the major mineralocorticoid in humans and paracellular pathways. The transcellular component and affects several of the cellular determinants discussed 1 is mediated by K transport on the apical membrane above, leading to stimulation of K1 secretion. First, aldo- 1 1 2 1 Na -K -2Cl cotransporter (Figure 4). K secretion begins sterone increases intracellular K1 concentration by stimu- in the early distal convoluted tubule and progressively lating the activity of the Na1-K1-ATPase in the basolateral increases along the distal nephron into the cortical collect- membrane. Second, aldosterone stimulates Na1 reabsorp- 1 ing duct (Figure 5). Most urinary K can be accounted for tion across the luminal membrane, which increases the 1 by electrogenic K secretion mediated by principal cells in electronegativity of the lumen, thereby increasing the elec- the initial collecting duct and the cortical collecting duct trical gradient favoring K1 secretion. Lastly, aldosterone (Figure 6). An electroneutral K1 and Cl2 cotransport has a direct effect on the luminal membrane to increase K1 mechanism is also present on the apical surface of the permeability (17).

1 1 1 Figure 3. | A cell model for K transport in the proximal tubule.K Figure 4. | AcellmodelforK transport in the thick ascending limb 1 reabsorption in the proximal tubule primarily occurs through the of Henle.K reabsorption occurs by both paracellular and trans- 1 1 1 paracellular pathway. Active Na reabsorption drives net fluid re- cellular mechanisms. The basolateral Na -K -ATPase pump main- 1 1 absorption across the proximal tubule, which in turn, drives K re- tains intracellular Na low, thus providing a favorable gradient to 1 1 2 absorption through a solvent drag mechanism. As fluid flows down drive the apically located Na -K -2Cl cotransporter (an example of the proximal tubule, the luminal voltage shifts from slightly negative secondary ). The apically located renal outer medul- 1 1 to slightly positive. The shift in transepithelial voltage provides an lary K (ROMK) channel provides a pathway for K to recycle 1 1 additional driving force favoring K through the low- from cell to lumen, and ensures an adequate supply of K to sustain 1 1 2 resistance paracellular pathway. Experimental studies suggest that Na -K -2Cl cotransport. This movement through ROMK creates 1 1 there may be a small component of transcellular K transport; how- a lumen-positive voltage, providing a driving force for passive K 1 1 ever, the significance of this pathway is not known. K uptake through reabsorption through the paracellular pathway. Some of the K entering 1 1 the Na -K -ATPase pump can exit the basolateral membrane through the cell through the cotransporter exits the cell across the basolateral 2 1 1 1 a conductive pathway or coupled to Cl . An apically located K membrane, accounting for transcellular K reabsorption. K can exit 2 channel functions to stabilize the cell negative potential, particularly the cell through a conductive pathway or in cotransport with Cl . 1 2 in the setting of Na -coupled cotransport of glucose and amino acids, ClC-Kb is the primary pathway for Cl efflux across the basolateral which has a depolarizing effect on cell voltage. membrane. 4 Clinical Journal of the American Society of Nephrology

1 Figure 6. | The cell that is responsible for K secretion in the initial collecting duct and the cortical collecting duct is the principal cell. 1 1 This cell possesses a basolateral Na -K -ATPase that is responsible 1 for the active transport of K from the blood into the cell. The resultant 1 high cell K concentration provides a favorable diffusion gradient for 1 movement of K from the cell into the lumen. In addition to estab- 1 lishing a high intracellular K concentration, activity of this pump 1 lowers intracellular Na concentration, thus maintaining a favorable 1 diffusion gradient for movement of Na from the lumen into the cell. 1 1 Both the movements of Na and K across the apical membrane 1 1 1 occur through well defined Na and K channels. Figure 5. | A cell model for K transport in the distal convoluted 1 tubule (DCT). In the early DCT, luminal Na uptake is mediated by 1 2 the apically located thiazide-sensitive Na -Cl cotransporter. The 1 1 transporter is energized by the basolateral Na -K -ATPase, which 1 maintains intracellular Na concentration low, thus providing a fa- 1 vorable gradient for Na 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 1 of the epithelial Na channel (ENaC), which mediates amiloride- 1 sensitive Na absorption, begins in the DCT2 and is robustly ex- pressed throughout the downstream connecting tubule and cortical collecting duct. The DCT2 is the beginning of the aldosterone- sensitive distal nephron (ASDN) as identified by the presence of both the mineralocorticoid receptor and the 11b-hydroxysteroid dehydrogenase II. This enzyme maintains the mineralocorticoid receptor free to only bind aldosterone by metabolizing cortisol to cor- tisone, the latter of which has no affinity for the receptor. Electrogenic- 1 mediated K transport begins in the DCT2 with the combined presence 1 2 Figure 7. | Reabsorption of HCO3 in the distal nephron is mediated of ROMK, ENaC, and aldosterone sensitivity. Electroneutral K -Cl 1 by apical H secretion by the a-intercalated cell. Two transporters cotransport is present in the DCT and collecting duct. Conditions 1 1 1 1 1 1 2 1 secrete H , a vacuolar H -ATPase and an H -K -ATPase. The H -K that cause a low luminal Cl concentration increase K secretion 1 -ATPase uses the energy derived from ATP hydrolysis to secrete H through this mechanism, which occurs with delivery of poorly re- 1 into the lumen and reabsorb K in an electroneutral fashion. The absorbable anions, such as sulfate, , or . 1 1 1 activity of the H -K -ATPase increases in K depletion and, thus, 1 provides a mechanism by which K depletion enhances both col- 1 1 lecting duct H secretion and K absorption. A second principal determinant affecting K1 secretion is the rate of distal delivery of Na1 and water. Increased Two populations of K1 channels have been identified in the distal delivery of Na1 stimulates distal Na1 absorption, cells of the cortical collecting duct. The renal outer medullary which will make the luminal potential more negative K1 (ROMK) channel is considered to be the major K1-secretory and, thus, increase K1 secretion. Increased flow rates pathway. This channel is characterized by having low con- also increase K1 secretion. When K1 is secreted in the ductance and a high probability of being open under phys- collecting duct, the luminal K1 concentration rises, which iologic conditions. The maxi-K1 channel (also known as the decreases the diffusion gradient and slows additional K1 large-conductance K1 [BK] channel) is characterized by a secretion. At higher luminal flow rates, the same amount large single channel conductance and quiescence in the basal of K1 secretion will be diluted by the larger volume such state and activation under conditions of increased flow (18). that the rise in luminal K1 concentration will be less. Thus, In addition to increased delivery of Na1 and dilution of increases in the distal delivery of Na1 and water stimulate luminal K1 concentration, recruitment of maxi-K1 channels K1 secretion by lowering luminal K1 concentration and contributes to flow-dependent increased K1 secretion. Renal making the luminal potential more negative. K1 channels are subjects of extensive reviews (19–21). Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 5

The effect of increased tubular flow to activate maxi-K1 of K1-secretory channels, helps maintain a state of positive channels may be mediated by changes in intracellular K1 balance during somatic growth after birth. These features Ca21 concentration (22). The channel is Ca21-activated, of distal K1 handling by the developing kidney are a likely and an acute increase in flow increases intracellular Ca21 explanation for the high incidence of nonoliguric hyperkale- concentrations in the principal cell. It has been suggested mia in preterm infants (29). that the central cilium (a structure present in principal Another physiologic state characterized by a period of cells) may facilitate transduction of signals of increased positive K1 balance is pregnancy, where approximately flow to increased intracellular Ca21 concentration. In cul- 300 mEq K1 is retained (30). High circulating levels of tured cells, bending of primary cilia results in a transient progesterone may play a role in this adaptation through increase in intracellular Ca21, an effect blocked by anti- stimulatory effects on K1 and H1 transport by the H1-K1 a bodies to (23). Although present in nearly 2-ATPase isoform in the distal nephron (31). all segments of the nephron, the maxi-K channel has In addition to stimulating maxi-K1 channels, increased been identified as the mediator of flow-induced K1 secre- tubular flow has been shown to stimulate Na1 absorption tion in the distal nephron and cortical collecting duct (24). through the epithelial Na1 channel (ENaC) in the collect- Development of hypokalemia in type II Bartter syn- ing duct. This increase in absorption not only is because of drome illustrates the importance of maxi-K1 channels in increased delivery of Na1, but also seems to be the result renal K1 excretion (25). Patients with type II Bartter syn- of mechanosensitive properties intrinsic to the channel. In- drome have a loss-of-function mutation in ROMK mani- creased flow creates a shear stress that activates ENaCs by festing with clinical features of the disease in the perinatal increasing channel open probability (32,33). 1 period. ROMK provides the pathway for recycling of K It has been hypothesized that biomechanical regulation of across the apical membrane in the thick ascending limb renal tubular Na1 and K1 transport in the distal nephron of Henle. This recycling generates a lumen-positive poten- may have evolved as a response to defend against sudden 1 tial that drives the paracellular reabsorption of Ca2 and increases in extracellular K1 concentration that occur in re- 1 1 1 1 2 Mg2 and provides luminal K to the Na -K -2Cl co- sponse to ingestion of K1-rich diets typical of early verte- transporter (Figure 4). brates (22). According to this hypothesis, an increase in GFR Mutations in ROMK decrease NaCl and fluid reabsorption after a protein-rich meal would lead to an increase in distal in the thick limb, mimicking a loop effect, which flow activating the ENaC, increasing intracellular Ca21 con- causes volume depletion. Despite the increase in distal Na1 centration, and activating maxi-K1 channels. These events delivery, K1 wasting is not consistently observed, because would enhance K1 secretion, thus providing a buffer to ROMK is also the major K1-secretory pathway for regulated guard against development of . K1 excretion in the collecting duct. In fact, in the perinatal In patients with CKD, loss of nephron mass is counter- period, infants with this form of often balanced by an adaptive increase in the secretory rate of K1 exhibit a transient hyperkalemia consistent with loss of func- in remaining such that K1 homeostasis is gener- tion of ROMK in the collecting duct. However, over time, ally well maintained until the GFR falls below 15–20 ml/ these patients develop hypokalemia as a result of increased min (34). The nature of the adaptive process is thought to flow-mediated K1 secretion through maxi-K1 channels. be similar to the adaptive process that occurs in response StudiesinanROMK-deficient mouse model of type II Bartter to high dietary K1 intake in normal subjects (35). Chronic syndrome are consistent with this mechanism (26). The K1 loading in animals augments the secretory capacity of transient hyperkalemia observed in the perinatal period is the distal nephron, and, therefore, renal K1 excretion is likely related to the fact that ROMK channels are function- significantly increased for any given plasma K1 level. In- ally expressed earlier than maxi-K1 channels during the creased K1 secretion under these conditions occurs in as- course of development. sociation with structural changes characterized by cellular In this regard, growing infants and children are in a state hypertrophy, increased mitochondrial density, and prolif- of positive K1 balance, which correlates with growth and eration of the basolateral membrane in cells in the distal increasing cell number. Early in development, there is a nephron and principal cells of the collecting duct. In- limited capacity of the distal nephron to secrete K1 because creased serum K1 and mineralocorticoids independently of a paucity of both apically located ROMK and maxi-K1 initiate the amplification process, which is accompanied by channels. The increase in K1-secretory capacity with matu- an increase in Na1-K1-ATPase activity. ration 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 Aldosterone Paradox in ref. 27). The limitation in distal K1 secretion is channel- Under conditions of volume depletion, activation of the specific, because the electrochemical gradient favoring K1 - system leads to increased aldosterone secretion, as determined by activity of the Na1-K1-ATPase release. The increase in circulating aldosterone stimulates and Na1 reabsorption, is not limiting. Additionally, in- renal Na1 retention, contributing to the restoration of ex- creased flow rates are accompanied by appropriate increases tracellular fluid volume, but occurs without a demonstra- in Na1 reabsorption and intracellular Ca21 concentrations in ble effect on renal K1 secretion. Under condition of the distal nephron, despite the absence of stimulatory effect hyperkalemia, aldosterone release is mediated by a direct on K1 secretion (28). Activity of the H1-K1-ATPase, which effect of K1 on cells in the zona glomerulosa. The subse- couples K1 reabsorption to H1 secretion in intercalated quent increase in circulating aldosterone stimulates renal cells, is similar in newborns and adults. K1 reabsorption K1 secretion, restoring the serum K1 concentration to nor- through this pump, combined with decreased expression mal, but does so without concomitant renal Na1 retention. 6 Clinical Journal of the American Society of Nephrology

The ability of aldosterone to signal the kidney to stim- the distal nephron (40,41). WNK4 is one of four members ulate salt retention without K1 secretioninvolumede- of a family of serine-threonine kinases each encoded by a pletion and stimulate K1 secretion without salt retention different and characterized by the atypical place- in hyperkalemia has been referred to as the aldosterone ment of the catalytic lysine residue that is present in paradox (36). In part, this ability can be explained by the most other protein kinases. Inactivating mutations in reciprocal relationship between urinary flow rates and dis- WNK4 lead to development of tal Na1 delivery with circulating aldosterone levels. Under type II (PHAII; Gordon syndrome). This disorder is in- conditions of volume depletion, proximal salt and water herited in an autosomal dominant fashion and is charac- absorption increase, resulting in decreased distal delivery terized by hypertension and hyperkalemia (42). of Na1 and water. Although aldosterone levels are in- Circulating aldosterone levels are low, despite the pres- creased, renal K1 excretion remains fairly constant, be- ence of hyperkalemia. Thiazide are particularly cause the stimulatory effect of increased aldosterone is effective in treating both the hypertension and hyperkale- counterbalanced by the decreased delivery of filtrate to mia (43). the distal nephron. Under condition of an expanded extra- Wild-type WNK4 acts to reduce surface expression of the cellular fluid volume, distal delivery of filtrate is increased thiazide-sensitive Na1-Cl2 cotransporter and also stimu- as a result of decreased proximal tubular fluid reabsorp- lates clathrin-dependent endocytosis of ROMK in the col- tion.Onceagain,renalK1 excretion remains relatively lecting duct (44,45). The inactivating mutation of WNK4 constant in this setting, because circulating aldosterone responsible for PHAII leads to increased cotransporter ac- levels are suppressed. It is only under pathophysiologic tivity and further stimulates endocytosis of ROMK. The conditions that increased distal Na1 and water delivery net effect is increased NaCl reabsorption combined with are coupled to increased aldosterone levels. Renal K1 decreased K1 secretion. Mutated WNK4 also enhances wasting will occur in this setting (37) (Figure 8). paracellular Cl2 permeability caused by increased phos- Renal K1 secretion also remains stable during changes phorylation of claudins, which are tight junction proteins in flow rate resulting from variations in circulating vaso- involved in regulating paracellular transport (46). In pressin. In this regard, has a stimulatory effect addition to increasing Na1 retention, this change in per- on renal K1 secretion (38,39). This kaliuretic property may meability further impairs K1 secretion, because the lumen- serve to oppose a tendency to K1 retention under condi- negative voltage, which normally serves as a driving force tions of antidiuresis when a low-flow rate-dependent fall for K1 secretion, is dissipated. in distal tubular K1 secretion might otherwise occur. In Because development of hypertension and hyperkalemia contrast, suppressed endogenous vasopressin leads to de- resulting from the PHAII-mutated WNK4 protein can be creased activity of the distal K1-secretory mechanism, thus viewed as an exaggerated response to a reduction in extra- limiting excessive K losses under conditions of full hydra- cellular fluid volume (salt retention without increased K1 tion and water . secretion), it has been proposed that wild-type WNK4 may Although the inverse relationship between aldosterone act as a molecular switch determining balance between renal levels and distal delivery of salt and water serves to keep NaCl reabsorption and K1 secretion (45,47). Under condi- renal K1 excretion independent of volume status, recent tions of volume depletion, the switch would be altered in a reviews have suggested a more complex mechanism cen- manner reminiscent of the PHAII mutant such that NaCl 1 tered on the with no lysine [K] 4 (WNK4) protein kinase in reabsorption is increased, but K secretion is further

1 Figure 8. | Under normal circumstances, delivery of Na to the distal nephron is inversely associated with serum aldosterone levels. For this 1 1 reason, renal K excretion is kept independent of changes in extracellular fluid volume. Hypokalemia caused by renal K wasting can be 1 explained by pathophysiologic changes that lead to coupling of increased distal Na delivery and aldosterone or aldosterone-like effects. 1 When approaching the hypokalemia caused by renal K wasting, one must determine whether the primary disorder is an increase in min- 1 eralocorticoid activity or an increase in distal Na delivery. EABV, effective arterial blood volume. Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 7

1 inhibited. However, when increased serum K concentration was largely caused by an increase in the K1 concentration occurs in the absence of volume depletion, WNK4 alterations in the cortical collecting duct. During this early phase, flow 1 1 result in maximal renal K secretion without Na retention. through the collecting duct increased only slightly, sug- Angiotensin II (AII) has emerged as an important gesting that changes in K1 concentration were largely modulator of this switch. Under conditions of volume caused by an increase in K1-secretory capacity of the col- depletion, AII and aldosterone levels are increased (Figure lecting duct. This effect would be consistent with known 9). In addition to effects leading to enhanced NaCl reab- effects of dietary supplementation of K1 to increase chan- sorption in the proximal tubule, AII activates the Na1-Cl2 nel density of both ROMK and maxi-K1 channels (56). cotransporter in a WNK4-dependent manner, and it is pri- In the subsequent 4 hours, renal K1 excretion continued marily located in the initial part of the distal convoluted to be high, but during this second phase, the kaliuresis was tubule (DCT; DCT1) (48,49). AII also activates ENaC, mostly accounted for by increased flow through the col- which is found in the aldosterone-sensitive distal nephron lecting duct. The increased flow was attributed to an in- (ASDN) comprised of the second segment of the DCT hibitory effect of increased interstitial K1 concentration on (DCT2), the connecting tubule, and the collecting duct reabsorption of NaCl in the upstream ascending limb of (50). The activation of ENaC by AII is additive to that of Henle, an effect supported by microperfusion studies in aldosterone (51). In this manner, AII and aldosterone act in the past (57,58). The timing of the two phases is presum- concert to stimulate Na1 retention. At the same time, AII in- ably important, because higher flows would be most effec- hibits ROMK by both WNK4-dependent and -independent tive in promoting kaliuresis only after establishment of mechanisms (52,53). This inhibitory effect on ROMK along increased channel density. Although older studies are con- with decreased Na1 delivery to the collecting duct brought sistent with decreased Na1 absorption in the thick limb about by AII stimulation of Na1 reabsorption in the prox- and proximal nephron after increased K1 intake, inhibi- imal nephron, and DCT1 allows for simultaneous Na1 con- tory effects in these high-capacity segments lack the pre- servation without K1 wasting. cision and timing necessary to ensure that downstream Hyperkalemia, or an increase in dietary K1 intake, can delivery of Na1 is appropriate to maximally stimulate increase renal K1 secretion independent of change in min- K1 secretion and at the same time, not be excessive, pre- eralocorticoid activity and without causing volume reten- disposing to volume depletion, particularly in the setting tion. This effect was shown in Wistar rats fed a diet very of a low Na1 diet (57–59). low in NaCl and K1 for several days and given a pharma- The low-capacity nature of the DCT and its location im- cologic dose of deoxycorticosterone to ensure a constant mediately upstream from the ASDN make this segment a and nonvariable effect of mineralocorticoids (54,55). more likely site for changes in dietary K1 intake to modulate After a KCl load administered into the peritoneal cavity, Na1 transport and ensure that downstream delivery of Na1 two distinct phases were noted. In the first 2 hours, there is precisely the amount needed to ensure maintenance of K1 was a large increase in the rate of renal K1 excretion that 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). 8 Clinical Journal of the American Society of Nephrology

In this regard, increased dietary K1 intake leads to an in- of ROMK, thus providing an appropriate response to limit hibitory effect on Na1 transport in this segment and does so K1 secretion. However, long WNK1 also leads to a stimu- through effects on WNK1, another member of the WNK latory effect on ENaC activity as well as releasing the in- family of kinases (60,61). WNK1 is ubiquitously expressed hibitory effect of WNK4 on Na1 reabsorption mediated by throughout the body in multiple spliced forms. By the NaCl cotransporter in the DCT (72,73). These effects contrast, a shorter WNK1 transcript lacking the amino ter- suggest that reductions in K1 secretion under conditions minal 1–437 amino acids of the long transcript is highly ex- of K1 deficiency will occur at the expense of increased Na1 pressed in the kidney but not other tissues, and it is referred retention. to as kidney-specific WNK1 (KS-WNK1). KS-WNK1 is re- Renal conservation of K1 and Na1 under conditions of K1 stricted to the DCT and part of the connecting duct and deficiency may be considered an evolutionary adaptation, functions as a physiologic antagonist to the actions of long because dietary K1 and Na1 deficiency likely occurred to- WNK1. Changes in the ratio of KS-WNK1 and long WNK1 gether for early humans (74). However, such an effect is in response to dietary K1 contribute to the physiologic reg- potentially deleterious in our present setting, because evolu- ulation of renal K1 excretion (62–65). tion has seen a large increase in the ratio of dietary intake of Under normal circumstances, long WNK1 prevents the Na1 versus K1. The effects of an increased ratio of WNK1 to ability of WNK4 to inhibit activity of the Na1-Cl2 cotrans- KS-WNK1 in the kidney under conditions of modern day porter in the DCT. Thus, increased activity of long WNK1 high Na1/low K1 diet could be central to the pathogenesis leads to a net increase in NaCl reabsorption. Dietary K1 of salt-sensitive hypertension (75). loading increases the abundance of KS-WNK1. Increased KS-WNK1 antagonizes the inhibitory effect of long WNK1 1 on WNK4. The net effect is inhibition of Na1-Cl2 cotrans- Enteric Sensor of K There is evidence to support the existence of enteric solute port in the DCT and increased Na1 delivery to more distal sensors capable of responding to dietary Na1,K1, and phos- parts of the tubule. In addition, increased KS-WNK1 an- phate that signal the kidney to rapidly alter ion excretion or tagonizes the effect of long WNK1 to stimulate endocyto- reabsorption (76–78). In experimental animals, and using sis of ROMK. Furthermore, KS-WNK1 exerts a stimulatory protocols to maintain identical plasma K1 concentration, effect on the ENaC. Thus, increases in KS-WNK1 in re- the kaliuretic response to a K1 load is greater when given sponse to dietary K1 loading facilitate K1 secretion as a meal compared with an intravenous infusion (79). These through the combined effects of increased Na1 delivery studies suggest that dietary K1 intake through a splanchnic throughdownregulationofNa1-Cl2 cotransport in the sensing mechanism can signal increases in renal K1 excre- DCT, increased electrogenic Na1 reabsorption through tion independent of changes in plasma K1 concentration or the ENaC, and greater abundance of ROMK. aldosterone (reviewed in ref. 80). Increased aldosterone levels in response to a high K1 diet Although the precise signaling mechanism is not known, lead to effects that complement the effects of KS-WNK1 recent studies suggest that the renal response may be (66,67). The serum- and -dependent protein because of rapid and nearly complete dephosphorylation of kinase (SGK1) is an immediate transcriptional target of al- the Na1-Cl2 cotransporter in the DCT, causing decreased dosterone binding to the mineralocorticoid receptor. Activa- activity of the transporter and, thus, enhancing delivery of tion of SGK1 leads to phosphorylation of WNK4, resulting Na1 to the ASDN (81,82). In these studies, gastric delivery in a loss of the ability of WNK4 to inhibit ROMK and the of K1 led to dephosphorylation of the cotransporter within ENaC (66,68). Aldosterone-induced activation of SGK1 also minutes independent of aldosterone and based on in vitro leads to increased ENaC expression and activity by causing studies, independent of changes in extracellular K1 con- the phosphorylation of ubiquitin protein ligase Nedd4–2. centration. The temporally associated increase in renal K1 Phosphorylated Nedd4–2 results in less retrieval of ENaC excretion results from a more favorable electrochemical from the apical membrane (69). It should be emphasized driving force caused by the downstream shift in Na1 re- that the absence of AII is a critical factor in the ability of absorption from the DCT to the ENaC in the ASDN as well high K1 intake to bring about the changes necessary to fa- as increased maxi-K1 channel K1 secretion brought on by cilitate K1 secretion without excessive Na1 reabsorption. 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. Role in Hypertension Changes in KS-WNK1 and long WNK1 that occur in response to dietary K1 intake affect renal Na1 handling Circadian Rhythm of K1 Secretion in a way that may be of importance in the observed re- During a 24-hour period, urinary K1 excretion varies in lationship between dietary K1 intake and hypertension. response to changes in activity and fluctuations in K1 intake Epidemiologic studies established that K1 intake is in- caused by the spacing of meals. However, even when K1 versely related to the prevalence of hypertension (70). In intake and activity are evenly spread over a 24-hour period, addition, K1 supplements and avoidance of hypokalemia there remains a circadian rhythm whereby K1 excretion is lowers BP in hypertensive subjects. By contrast, BP in- lower at night and in the early morning hours and then in- creases in hypertensive subjects placed on a low K1 diet. creases in the afternoon (83–86). This circadian pattern results This increase in BP is associated with increased renal Na1 from changes in intratubular K1 concentration in the collect- reabsorption (71). ing duct as opposed to variations in flow rate (87). K1 deficiency increases the ratio of long WNK1 to In the mouse distal nephron, a circadian rhythm exists KS-WNK1. Long WNK1 is associated with increased retrieval for gene transcripts that encode proteins involving K1 Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 9

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