Renal CJASN

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

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 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
Introduction Catecholamines regulate internal K1 distribution, with Internal Medicine,
Potassium plays a key role in maintaining cell function. a-adrenergic receptors impairing and b-adrenergic recep- University of Texas
Almost all cells possess an Na1-K1-ATPase, which tors promoting cellular entry of K1. b2-Receptor–induced Southwestern Medical
Center, 5323 Harry
pumps Na1 out of the cell and K1 into the cell and stimulation of K1 uptake is mediated by activation of the Hines Boulevard,
leads to a K1 gradient across the cell membrane (K1in. Na1-K1-ATPase pump. These effects play a role in reg- Dallas, TX 75390.
K1out) that is partially responsible for maintaining the ulating the cellular release of K1 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- can be as high as 10–12 mM with severe exercise.
fense of serum K 1 . These mechanisms serve to Accumulation of K1 is a factor limiting the excitabil-
maintain a proper distribution of K1 within the body ity and contractile force of muscle accounting for the
as well as regulate the total body K1 content. development of fatigue (7,8). Additionally, increases
in interstitial K1 play a role in eliciting rapid vaso-
Internal Balance of K1 dilation, allowing for blood flow to increase in exer-
The kidney is primarily responsible for maintaining cising muscle (9). During exercise, release of
total body K1 content by matching K1 intake with K1 catecholamines through b2 stimulation limits the
excretion. Adjustments in renal K1 excretion occur rise in extracellular K1 concentration that otherwise
over several hours; therefore, changes in extracellular occurs as a result of normal K1 release by contracting
K1 concentration are initially buffered by movement muscle. Although the mechanism is likely to be mul-
of K1 into or out of skeletal muscle. The regulation of tifactorial, total body K1 depletion may blunt the ac-
K1 distribution between the intracellular and extracel- cumulation of K1 into the interstitial space, limiting
lular space is referred to as internal K1 balance. The blood flow to skeletal muscle and accounting for the
most important factors regulating this movement under association of hypokalemia with rhabdomyolysis.
normal conditions are insulin and catecholamines (1). Changes in plasma tonicity and acid–base disorders
After a meal, the postprandial release of insulin also influence internal K1 balance. Hyperglycemia
functions to not only regulate the serum glucose leads to water movement from the intracellular to
concentration but also shift dietary K1 into cells until extracellular compartment. This water movement fa-
the kidney excretes the K1 load re-establishing K1 ho- vors K1 efflux from the cell through the process of
meostasis. These effects are mediated through insulin solvent drag. In addition, cell shrinkage causes intra-
binding to cell surface receptors, which stimulates glu- cellular K1 concentration to increase, creating a more
cose uptake in insulin-responsive tissues through the favorable concentration gradient for K1 efflux. Min-
insertion of the glucose transporter protein GLUT4 eral acidosis, but not organic acidosis, can be a cause
(2,3). An increase in the activity of the Na1-K1-AT- of cell shift in K1. As recently reviewed, the general
1
Pase mediates K uptake (Figure 1). In patients with effect of acidemia to cause K1 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 Nephrology 1
2 Clinical Journal of the American Society of Nephrology

Figure 1. | The cell model illustrates b2-adrenergic and insulin-

mediated 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 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).

Intracellular K1 serves as a reservoir to limit the fall in
extracellular K1 concentrations occurring under patho-
logic 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 concentra-
tion despite daily sweat K1 loses of .40 mmol and an 11-
day cumulative total body K1 deficit of approximately 400
mmol.
Studies in rats using a K1 clamp technique afforded in-
sight into the role of skeletal muscle in regulating extracel-
lular 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 pre-
sumed to be equal to the amount of K1 entering the in-
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-
mediated 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 ex-
tracellular 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 in-
tracellular Na1 will reduce Na1-K1-ATPase activity, causing a net
loss of cellular K1. In addition, the fall in extracellular HCO3 concen-
tration 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 or-
ganic 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 in-
tracellular Na1 maintains Na1-K1-ATPase activity, thereby mini-
mizing any change in extracellular K1 concentration.
expression and activity facilitate the ability of skeletal muscle
to buffer declines in extracellular K1 concentrations by do-
nating 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 con-
tent 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
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015
increases in K1-deficient animals. This difference explains
the greater total K1 clearance capacity after the acute ad-
ministration 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 compa-
rable with that of skeletal muscle under conditions of K1
depletion and may actually exceed skeletal muscle under
control conditions.
Renal Potassium Handling
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 collect-
ing 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
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 re-
absorption across the proximal tubule, which in turn, drives K1 re-
absorption 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 low-
resistance paracellular pathway. Experimental studies suggest that
there may be a small component of transcellular K1 transport; how-
ever, 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.
Normal Potassium Homeostasis, Palmer 3
distal nephron (15). Under conditions of K1 depletion, re-
absorption 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 con-
trast, 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 mem-
brane, and the permeability of the luminal membrane for
K1. Conditions that increase cellular K1 concentration, de-
crease luminal K1 concentration, or render the lumen more
electronegative will increase the rate of K1 secretion. Con-
ditions that increase the permeability of the luminal mem-
brane 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, aldo-
sterone increases intracellular K1 concentration by stimu-
lating the activity of the Na1-K1-ATPase in the basolateral
membrane. Second, aldosterone stimulates Na1 reabsorp-
tion across the luminal membrane, which increases the
electronegativity of the lumen, thereby increasing the elec-
trical gradient favoring K1 secretion. Lastly, aldosterone
has a direct effect on the luminal membrane to increase K1
permeability (17).
Figure 4. | A cell model for K1 transport in the thick ascending limb
of Henle. K1 reabsorption occurs by both paracellular and trans-
cellular mechanisms. The basolateral Na1-K1-ATPase pump main-
tains 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 medul-
lary 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.
4 Clinical Journal of the American Society of Nephrology
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 fa-
vorable 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 amiloride-
sensitive Na1 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 enzyme 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-
mediated 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 re-
absorbable 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 estab-
lishing 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 col-
lecting 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 con-
ductance and a high probability of being open under phys-
iologic 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).
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015
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 cul-
tured cells, bending of primary cilia results in a transient
increase in intracellular Ca21, an effect blocked by anti-
bodies 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 secre-
tion in the distal nephron and cortical collecting duct (24).
Development of hypokalemia in type II Bartter syn-
drome illustrates the importance of maxi-K1 channels in
renal K1 excretion (25). Patients with type II Bartter syn-
drome have a loss-of-function mutation in ROMK mani-
festing 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 poten-
tial that drives the paracellular reabsorption of Ca21 and
Mg21 and provides luminal K1 to the Na1-K1-2Cl2 co-
transporter (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 func-
tion 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 function-
ally 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 matu-
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
in ref. 27). The limitation in distal K1 secretion is channel-
specific, because the electrochemical gradient favoring K1
secretion, as determined by activity of the Na1-K1-ATPase
and Na1 reabsorption, is not limiting. Additionally, in-
creased 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
Normal Potassium Homeostasis, Palmer 5
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 hyperkale-
mia 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 collect-
ing 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. In-
creased 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 re-
sponse to ingestion of K1-rich diets typical of early verte-
brates (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 con-
centration, 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 counter-
balanced by an adaptive increase in the secretory rate of K1
in remaining nephrons such that K1 homeostasis is gener-
ally 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. In-
creased K1 secretion under these conditions occurs in as-
sociation with structural changes characterized by cellular
hypertrophy, increased mitochondrial density, and prolif-
eration of the basolateral membrane in cells in the distal
nephron and principal cells of the collecting duct. In-
creased 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 ex-
tracellular fluid volume, but occurs without a demonstra-
ble 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 subse-
quent increase in circulating aldosterone stimulates renal
K1 secretion, restoring the serum K1 concentration to nor-
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-
ulate salt retention without K1 secretion in volume de-
pletion 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 dis-
tal 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 in-
creased, renal K1 excretion remains fairly constant, be-
cause the stimulatory effect of increased aldosterone is
counterbalanced by the decreased delivery of filtrate to
the distal nephron. Under condition of an expanded extra-
cellular fluid volume, distal delivery of filtrate is increased
as a result of decreased proximal tubular fluid reabsorp-
tion. 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 vaso-
pressin. 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 condi-
tions of antidiuresis when a low-flow rate-dependent fall
in distal tubular K1 secretion might otherwise occur. In
contrast, suppressed endogenous vasopressin leads to de-
creased activity of the distal K1-secretory mechanism, thus
limiting excessive K losses under conditions of full hydra-
tion 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 cen-
tered 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 place-
ment 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 in-
herited in an autosomal dominant fashion and is charac-
terized by hypertension and hyperkalemia (42).
Circulating aldosterone levels are low, despite the pres-
ence of hyperkalemia. Thiazide diuretics are particularly
effective in treating both the hypertension and hyperkale-
mia (43).
Wild-type WNK4 acts to reduce surface expression of the
thiazide-sensitive Na1-Cl2 cotransporter and also stimu-
lates clathrin-dependent endocytosis of ROMK in the col-
lecting duct (44,45). The inactivating mutation of WNK4
responsible for PHAII leads to increased cotransporter ac-
tivity 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 phos-
phorylation of claudins, which are tight junction proteins
involved in regulating paracellular ion transport (46). In
addition to increasing Na1 retention, this change in per-
meability further impairs K1 secretion, because the lumen-
negative 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 extra-
cellular 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 condi-
tions 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 min-
eralocorticoid activity or an increase in distal Na1 delivery. EABV, effective arterial blood volume.
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 7

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 reab-
sorption in the proximal tubule, AII activates the Na1-Cl2
cotransporter in a WNK4-dependent manner, and it is pri-
marily 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 in-
hibits 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 prox-
imal nephron, and DCT1 allows for simultaneous Na1 con-
servation without K1 wasting.
Hyperkalemia, or an increase in dietary K1 intake, can
increase renal K1 secretion independent of change in min-
eralocorticoid activity and without causing volume reten-
tion. This effect was shown in Wistar rats fed a diet very
low in NaCl and K1 for several days and given a pharma-
cologic 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
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, sug-
gesting that changes in K1 concentration were largely
caused by an increase in K1-secretory capacity of the col-
lecting duct. This effect would be consistent with known
effects of dietary supplementation of K1 to increase chan-
nel 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 col-
lecting duct. The increased flow was attributed to an in-
hibitory 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 presum-
ably important, because higher flows would be most effec-
tive in promoting kaliuresis only after establishment of
increased channel density. Although older studies are con-
sistent with decreased Na1 absorption in the thick limb
and proximal nephron after increased K1 intake, inhibi-
tory effects in these high-capacity segments lack the pre-
cision 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, pre-
disposing to volume depletion, particularly in the setting
of a low Na1 diet (57–59).
The low-capacity nature of the DCT and its location im-
mediately 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).
8 Clinical Journal of the American Society of Nephrology
In this regard, increased dietary K1 intake leads to an in-
hibitory 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 ter-
minal 1–437 amino acids of the long transcript is highly ex-
pressed in the kidney but not other tissues, and it is referred
to as kidney-specific WNK1 (KS-WNK1). KS-WNK1 is re-
stricted 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 reg-
ulation of renal K1 excretion (62–65).
Under normal circumstances, long WNK1 prevents the
ability of WNK4 to inhibit activity of the Na1-Cl2 cotrans-
porter 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 cotrans-
port in the DCT and increased Na1 delivery to more distal
parts of the tubule. In addition, increased KS-WNK1 an-
tagonizes the effect of long WNK1 to stimulate endocyto-
sis of ROMK. Furthermore, KS-WNK1 exerts a stimulatory
effect on the ENaC. Thus, increases in KS-WNK1 in re-
sponse 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 al-
dosterone binding to the mineralocorticoid receptor. Activa-
tion 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 fa-
cilitate 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 re-
lationship between dietary K1 intake and hypertension.
Epidemiologic studies established that K1 intake is in-
versely related to the prevalence of hypertension (70). In
addition, K1 supplements and avoidance of hypokalemia
lowers BP in hypertensive subjects. By contrast, BP in-
creases 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 stimu-
latory effect on ENaC activity as well as releasing the in-
hibitory 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 to-
gether for early humans (74). However, such an effect is
potentially deleterious in our present setting, because evolu-
tion 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 phos-
phate 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 excre-
tion 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 con-
centration. The temporally associated increase in renal K1
excretion results from a more favorable electrochemical
driving force caused by the downstream shift in Na1 re-
absorption 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 in-
creases in the afternoon (83–86). This circadian pattern results
from changes in intratubular K1 concentration in the collect-
ing 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
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015
secretion (88). Gene expression of ROMK is greater during
periods of activity, whereas expression of the H1-K1-AT-
Pase 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 con-
tributory 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 reg-
ulating 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 sug-
gests that dysregulation of circadian rhythms may contrib-
ute to a lack of nocturnal decline in BP, with eventual
development of sustained hypertension as well as acceler-
ated 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 reg-
ulated 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 exer-
cise. J Physiol 583: 825–833, 2007
10. Aronson PS, Giebisch G: Effects of pH on potassium: New ex-
planations 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 potas-
sium depletion. J Clin Invest 51: 242–255, 1972
12. McDonough AA, Youn JH: Role of muscle in regulating extra-
cellular [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 re-
pletion. Am J Physiol Cell Physiol 283: C1163–C1170, 2002
14. Bundgaard H: Potassium depletion improves myocardial potas-
sium uptake in vivo. Am J Physiol Cell Physiol 287: C135–C141,
2004
15. Velázquez H, Ellison DH, Wright FS: Chloride-dependent po-
tassium 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
Normal Potassium Homeostasis, Palmer 9
18. Palmer LG, Frindt G: High-conductance K channels in in-
tercalated cells of the rat distal nephron. Am J Physiol Renal
Physiol 292: F966–F973, 2007
19. Hebert SC, Desir G, Giebisch G, Wang W: Molecular diversity
and regulation of renal potassium channels. Physiol Rev 85: 319–
371, 2005
20. Wang WH: Regulation of ROMK (Kir1.1) channels: New mech-
anisms and aspects. Am J Physiol Renal Physiol 290: F14–F19,
2006
21. Grimm PR, Sansom SC: BK channels in the kidney. Curr Opin
Nephrol Hypertens 16: 430–436, 2007
22. Satlin LM, Carattino MD, Liu W, Kleyman TR: Regulation of
cation transport in the distal nephron by mechanical forces. Am J
Physiol Renal Physiol 291: F923–F931, 2006
23. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE,
Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J: Polycystins 1 and
2 mediate mechanosensation in the primary cilium of kidney
cells. Nat Genet 33: 129–137, 2003
24. Welling PA: Regulation of renal potassium secretion: Molecular
mechanisms. Semin Nephrol 33: 215–228, 2013
25. Pluznick JL, Sansom SC: BK channels in the kidney: Role in K(1)
secretion and localization of molecular components. Am J
Physiol Renal Physiol 291: F517–F529, 2006
26. Bailey MA, Cantone A, Yan Q, MacGregor GG, Leng Q, Amorim
JB, Wang T, Hebert SC, Giebisch G, Malnic G: Maxi-K channels
contribute to urinary potassium excretion in the ROMK-
deficient mouse model of Type II Bartter’s syndrome and in
adaptation to a high-K diet. Kidney Int 70: 51–59, 2006
27. Gurkan S, Estilo GK, Wei Y, Satlin LM: Potassium transport in the
maturing kidney. Pediatr Nephrol 22: 915–925, 2007
28. Woda CB, Miyawaki N, Ramalakshmi S, Ramkumar M, Rojas R,
Zavilowitz B, Kleyman TR, Satlin LM: Ontogeny of flow-stimulated
potassium secretion in rabbit cortical collecting duct: Functional
and molecular aspects. Am J Physiol Renal Physiol 285: F629–
F639, 2003
29. Thayyil S, Kempley ST, Sinha A: Can early-onset nonoliguric
hyperkalemia be predicted in extremely premature infants? Am J
Perinatol 25: 129–133, 2008
30. Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI: Potassium
homeostasis in pregnancy. J Reprod Med 32: 517–522, 1987
31. Elabida B, Edwards A, Salhi A, Azroyan A, Fodstad H, Meneton P,
Doucet A, Bloch-Faure M, Crambert G: Chronic potassium de-
pletion increases adrenal progesterone production that is nec-
essary for efficient renal retention of potassium. Kidney Int 80:
256–262, 2011
32. Morimoto T, Liu W, Woda C, Carattino MD, Wei Y, Hughey RP,
Apodaca G, Satlin LM, Kleyman TR: Mechanism underlying flow
stimulation of sodium absorption in the mammalian collecting
duct. Am J Physiol Renal Physiol 291: F663–F669, 2006
33. Carattino MD, Sheng S, Kleyman TR: Mutations in the pore re-
gion modify epithelial sodium channel gating by shear stress.
J Biol Chem 280: 4393–4401, 2005
34. van Ypersele de Strihou C: Potassium homeostasis in renal fail-
ure. Kidney Int 11: 491–504, 1977
35. Stanton BA: Renal potassium transport: Morphological and
functional adaptations. Am J Physiol 257: R989–R997, 1989
36. Arroyo JP, Ronzaud C, Lagnaz D, Staub O, Gamba G: Aldoste-
rone paradox: Differential regulation of ion transport in distal
nephron. Physiology (Bethesda) 26: 115–123, 2011
37. Palmer BF: A physiologic-based approach to the evaluation of a
patient with hypokalemia. Am J Kidney Dis 56: 1184–1190, 2010
38. Field MJ, Stanton BA, Giebisch GH: Influence of ADH on renal
potassium handling: A micropuncture and microperfusion study.
Kidney Int 25: 502–511, 1984
39. Cassola AC, Giebisch G, Wang W: Vasopressin increases density
of apical low-conductance K1 channels in rat CCD. Am J Physiol
264: F502–F509, 1993
40. Kahle KT, Ring AM, Lifton RP: Molecular physiology of the WNK
kinases. Annu Rev Physiol 70: 329–355, 2008
41. Kahle KT, Rinehart J, Giebisch G, Gamba G, Hebert SC, Lifton RP:
A novel protein kinase signaling pathway essential for blood
pressure regulation in humans. Trends Endocrinol Metab 19: 91–
95, 2008
42. Mayan H, Vered I, Mouallem M, Tzadok-Witkon M, Pauzner R,
Farfel Z: Pseudohypoaldosteronism type II: Marked sensitivity to
10 Clinical Journal of the American Society of Nephrology
thiazides, hypercalciuria, normomagnesemia, and low bone
mineral density. J Clin Endocrinol Metab 87: 3248–3254, 2002
43. Gordon RD: The syndrome of hypertension and hyperkalaemia
with normal GFR. A unique pathophysiological mechanism for
hypertension? Clin Exp Pharmacol Physiol 13: 329–333, 1986
44. Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida
K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S:
Molecular pathogenesis of pseudohypoaldosteronism type II:
Generation and analysis of a Wnk4(D561A/1) knockin mouse
model. Cell Metab 5: 331–344, 2007
45. Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka
HR, Nelson-Williams C, Ellison DH, Flavell R, Booth CJ, Lu Y,
Geller DS, Lifton RP: Wnk4 controls blood pressure and potas-
sium homeostasis via regulation of mass and activity of the distal
convoluted tubule. Nat Genet 38: 1124–1132, 2006
46. Yamauchi K, Rai T, Kobayashi K, Sohara E, Suzuki T, Itoh T, Suda S,
Hayama A, Sasaki S, Uchida S: Disease-causing mutant WNK4
increases paracellular chloride permeability and phosphorylates
claudins. Proc Natl Acad Sci U S A 101: 4690–4694, 2004
47. Kahle KT, Wilson FH, Lifton RP: Regulation of diverse ion
transport pathways by WNK4 kinase: A novel molecular switch.
Trends Endocrinol Metab 16: 98–103, 2005
48. Casta~neda-Bueno M, Gamba G: Mechanisms of sodium-chloride
cotransporter modulation by angiotensin II. Curr Opin Nephrol
Hypertens 21: 516–522, 2012
49. Casta~neda-Bueno M, Cervantes-Pérez LG, Vázquez N, Uribe N,
Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR,
Gamba G: Activation of the renal Na1:Cl- cotransporter by an-
giotensin II is a WNK4-dependent process. Proc Natl Acad Sci
U S A 109: 7929–7934, 2012
50. Sun P, Yue P, Wang WH: Angiotensin II stimulates epithelial so-
dium channels in the cortical collecting duct of the rat kidney.
Am J Physiol Renal Physiol 302: F679–F687, 2012
51. van der Lubbe N, Zietse R, Hoorn EJ: Effects of angiotensin II on
kinase-mediated sodium and potassium transport in the distal
nephron. Curr Opin Nephrol Hypertens 22: 120–126, 2013
52. Wei Y, Zavilowitz B, Satlin LM, Wang WH: Angiotensin II inhibits
the ROMK-like small conductance K channel in renal cortical
collecting duct during dietary potassium restriction. J Biol Chem
282: 6455–6462, 2007
53. Yue P, Sun P, Lin DH, Pan C, Xing W, Wang W: Angiotensin II
diminishes the effect of SGK1 on the WNK4-mediated inhibition
of ROMK1 channels. Kidney Int 79: 423–431, 2011
54. Halperin ML, Cheema-Dhadli S, Lin SH, Kamel KS: Control of
potassium excretion: A Paleolithic perspective. Curr Opin
Nephrol Hypertens 15: 430–436, 2006
55. Cheema-Dhadli S, Lin SH, Keong-Chong C, Kamel KS, Halperin
ML: Requirements for a high rate of potassium excretion in rats
consuming a low electrolyte diet. J Physiol 572: 493–501, 2006
56. Najjar F, Zhou H, Morimoto T, Bruns JB, Li HS, Liu W, Kleyman
TR, Satlin LM: Dietary K1 regulates apical membrane expression
of maxi-K channels in rabbit cortical collecting duct. Am J
Physiol Renal Physiol 289: F922–F932, 2005
57. Stokes JB: Consequences of potassium recycling in the renal
medulla. Effects of ion transport by the medullary thick ascending
limb of Henle’s loop. J Clin Invest 70: 219–229, 1982
58. Sufit CR, Jamison RL: Effect of acute potassium load on re-
absorption in Henle’s loop in the rat. Am J Physiol 245: F569–
F576, 1983
59. Brandis M, Keyes J, Windhager EE: Potassium-induced inhibition
of proximal tubular fluid reabsorption in rats. Am J Physiol 222:
421–427, 1972
60. Cheng CJ, Truong T, Baum M, Huang CL: Kidney-specific WNK1
inhibits sodium reabsorption in the cortical thick ascending limb.
Am J Physiol Renal Physiol 303: F667–F673, 2012
61. Liu Z, Xie J, Wu T, Truong T, Auchus RJ, Huang CL: Down-
regulation of NCC and NKCC2 cotransporters by kidney-specific
WNK1 revealed by gene disruption and transgenic mouse
models. Hum Mol Genet 20: 855–866, 2011
62. O’Reilly M, Marshall E, Macgillivray T, Mittal M, Xue W, Kenyon
CJ, Brown RW: Dietary electrolyte-driven responses in the
renal WNK kinase pathway in vivo. J Am Soc Nephrol 17: 2402–
2413, 2006
63. Wade JB, Fang L, Liu J, Li D, Yang CL, Subramanya AR, Maouyo D,
Mason A, Ellison DH, Welling PA: WNK1 kinase isoform switch
regulates renal potassium excretion. Proc Natl Acad Sci U S A
103: 8558–8563, 2006
64. Lazrak A, Liu Z, Huang CL: Antagonistic regulation of ROMK by
long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci
U S A 103: 1615–1620, 2006
65. Cope G, Murthy M, Golbang AP, Hamad A, Liu CH, Cuthbert AW,
O’Shaughnessy KM: WNK1 affects surface expression of the
ROMK potassium channel independent of WNK4. J Am Soc
Nephrol 17: 1867–1874, 2006
66. Ring AM, Leng Q, Rinehart J, Wilson FH, Kahle KT, Hebert SC,
Lifton RP: An SGK1 site in WNK4 regulates Na1 channel and
K1 channel activity and has implications for aldosterone signaling
and K1 homeostasis. Proc Natl Acad Sci U S A 104: 4025–4029,
2007
67. Náray-Fejes-Tóth A, Snyder PM, Fejes-Tóth G: The kidney-specific
WNK1 isoform is induced by aldosterone and stimulates epithelial
sodium channel-mediated Na1 transport. Proc Natl Acad Sci
U S A 101: 17434–17439, 2004
68. Lin DH, Yue P, Rinehart J, Sun P, Wang Z, Lifton R, Wang WH:
Protein phosphatase 1 modulates the inhibitory effect of
With-no-Lysine kinase 4 on ROMK channels. Am J Physiol Renal
Physiol 303: F110–F119, 2012
69. Palmer BF, Alpern RJ: Liddle’s syndrome. Am J Med 104: 301–
309, 1998
70. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM;
American Heart Association: Dietary approaches to prevent and
treat hypertension: A scientific statement from the American
Heart Association. Hypertension 47: 296–308, 2006
71. Krishna GG, Kapoor SC: Potassium depletion exacerbates es-
sential hypertension. Ann Intern Med 115: 77–83, 1991
72. Vallon V, Wulff P, Huang DY, Loffing J, Völkl H, Kuhl D, Lang F:
Role of Sgk1 in salt and potassium homeostasis. Am J Physiol
Regul Integr Comp Physiol 288: R4–R10, 2005
73. Rozansky DJ: The role of aldosterone in renal sodium transport.
Semin Nephrol 26: 173–181, 2006
74. Eaton SB: The ancestral human diet: What was it and should it be a
paradigm for contemporary nutrition? Proc Nutr Soc 65: 1–6, 2006
75. Huang CL, Kuo E: Mechanisms of disease: WNK-ing at the
mechanism of salt-sensitive hypertension. Nat Clin Pract Nephrol
3: 623–630, 2007
76. Thomas L, Kumar R: Control of renal solute excretion by enteric
signals and mediators. J Am Soc Nephrol 19: 207–212, 2008
77. Michell AR, Debnam ES, Unwin RJ: Regulation of renal
function by the gastrointestinal tract: Potential role of gut-
derived peptides and hormones. Annu Rev Physiol 70: 379–
403, 2008
78. Lee FN, Oh G, McDonough AA, Youn JH: Evidence for gut factor in
K1 homeostasis. Am J Physiol Renal Physiol 293: F541–F547, 2007
79. Oh KS, Oh YT, Kim SW, Kita T, Kang I, Youn JH: Gut sensing of
dietary K⁺ intake increases renal K⁺ excretion. Am J Physiol Regul
Integr Comp Physiol 301: R421–R429, 2011
80. Youn JH: Gut sensing of potassium intake and its role in potas-
sium homeostasis. Semin Nephrol 33: 248–256, 2013
81. Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP,
Barmettler G, Ziegler U, Odermatt A, Loffing-Cueni D, Loffing J:
Rapid dephosphorylation of the renal sodium chloride co-
transporter in response to oral potassium intake in mice. Kidney
Int 83: 811–824, 2013
82. McDonough AA, Youn JH: Need to quickly excrete K(1)? Turn off
NCC. Kidney Int 83: 779–782, 2013
83. Firsov D, Tokonami N, Bonny O: Role of the renal circadian
timing system in maintaining water and electrolytes homeostasis.
Mol Cell Endocrinol 349: 51–55, 2012
84. Firsov D, Bonny O: Circadian regulation of renal function. Kid-
ney Int 78: 640–645, 2010
85. Bonny O, Firsov D: Circadian regulation of renal function and
potential role in hypertension. Curr Opin Nephrol Hypertens 22:
439–444, 2013
86. Gumz ML, Rabinowitz L: Role of circadian rhythms in potassium
homeostasis. Semin Nephrol 33: 229–236, 2013
87. Steele A, deVeber H, Quaggin SE, Scheich A, Ethier J, Halperin
ML: What is responsible for the diurnal variation in potassium
excretion? Am J Physiol 267: R554–R560, 1994
88. Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L,
Cardinaux L, Bonny O, Firsov D: Molecular clock is involved in
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015
predictive circadian adjustment of renal function. Proc Natl
Acad Sci U S A 106: 16523–16528, 2009
89. Salhi A, Centeno G, Firsov D, Crambert G: Circadian expression
of H,K-ATPase type 2 contributes to the stability of plasma K⁺
levels. FASEB J 26: 2859–2867, 2012
90. Gumz ML, Stow LR, Lynch IJ, Greenlee MM, Rudin A, Cain BD,
Weaver DR, Wingo CS: The circadian clock protein Period 1
regulates expression of the renal epithelial sodium channel in
mice. J Clin Invest 119: 2423–2434, 2009
91. Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M,
Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S,
Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S:
Normal Potassium Homeostasis, Palmer 11
Impaired KLHL3-mediated ubiquitination of WNK4 causes
human hypertension. Cell Rep 3: 858–868, 2013
92. Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP: Kelch-like 3
and Cullin 3 regulate electrolyte homeostasis via ubiquitination
and degradation of WNK4. Proc Natl Acad Sci U S A 110:
7838–7843, 2013
93. Hoorn EJ, Nelson JH, McCormick JA, Ellison DH: The WNK ki-
nase network regulating sodium, potassium, and blood pressure.
J Am Soc Nephrol 22: 605–614, 2011
Published online ahead of print. Publication date available at www.
cjasn.org.