Renal

Abstract
The regulation of potassium metabolism involves mechanisms for the appropriate distribution
between the intra- and extracellular fluid compartments and for the excretion by the kidney.
Clearance and single-nephron studies show that renal excretion is determined by regulated
potassium secretion and potassium reabsorption, respectively, in principal and intercalated cells
of the distal nephron. Measurement of the electrochemical driving forces acting on potassium
transport across individual cell membranes and characterization of several ATPases and
potassium channels provide insights into the transport and regulation of renal potassium
excretion.
the physiological regulation of potassium, the most abundant cation in the body, requires
achievement of two goals. First, high concentrations of potassium in the cytosol are necessary for
many cells to function normally (130). Second, sizable concentration gradients of potassium
across cell membranes are required for nerve excitation and muscle contraction. This condition
can be met only by mechanisms that maintain low extracellular potassium concentrations.
Accordingly, two internal milieus, intracellular and extracellular fluid, are continuously and
separately controlled to safeguard potassium homeostasis.
An understanding of potassium homeostasis requires considering the special distribution of

potassium in the body. Figure1 A shows that the vast majority of potassium is contained by cells;
only a very small fraction, some 1–2% of total potassium, is located in the extracellular fluid
(110, 130). The small extracellular pool can be greatly increased from two sources: external
intake and internal redistribution. An intake of 35 meq, about one-third of the normal daily
intake of potassium, would produce an increase of plasma potassium of about 2.5 meq/l, were
that amount confined exclusively to the extracellular fluid. Such a rise in plasma potassium could
have pronounced deleterious effects on neuromuscular and cardiac function. However, the
apparent volume of distribution of an oral potassium load is greatly in excess of the extracellular
fluid compartment: rapid redistribution into tissue stores, particularly those of muscle and liver,
provide protection against unphysiological fluctuations of plasma potassium concentrations. The
most important of the mechanisms that modulate the distribution of potassium between the extra-
and intracellular compartment are listed in Fig.1 B (18,110, 130).
 Download figure
 Open in new tab
 Download powerpoint
 Download figure
 Open in new tab
Fig. 1.
A: potassium homeostasis depends on maintenance of external and internal potassium balance.

External potassium balance is determined by rate of potassium intake (100 meq/day) and rate of
urinary (90 meq/day) and fecal excretion (10 meq/day). Internal potassium balance depends on
distribution of potassium between muscle, bone, liver, and red blood cells (RBC) and the
extracellular fluid (ECF). This distribution is regulated by several hormones and is affected by
acid-base balance and tonicity of plasma. (Movement of potassium between the ECF and cells is
indicated by the small arrows.) [Modified from Stanton and Giebisch (130).] B: factors affecting
potassium distribution between extra- and intracellular fluid (18, 41,110).
The internal balance of potassium can also be severely disturbed whenever those mechanisms
that retain large amounts of potassium within cells are compromised. Accordingly, interference
with Na-K-ATPase activity or abnormal leakiness of cells to potassium, as may occur when there
is extensive cell damage, always pose the threat of acute hyperkalemia by possibly lethal mixing
between intra- and extracellular potassium pools (50, 110, 130).
The two mechanisms that counter changes in plasma potassium concentration are distinguished
by different time courses: an excess or deficit of potassium in the extracellular fluid can be
rapidly, within minutes, corrected by appropriate shifts into or out of body stores. The renal
response is much slower, and renal corrections of disturbances in potassium balance require
several hours (110, 130).
Approaches to the Study of Renal Potassium Excretion
Advances in our knowledge of the renal mechanisms of potassium excretion have depended on
the application of a wide variety of techniques, summarized in Table 1. The modern period of
investigation into modes of potassium transport by the kidney begins with the use of the flame
photometer in the late 1940s and the application of clearance methods (7, 8, 97, 98). The
comparison of the excreted with the filtered amounts demonstrated that the kidney tubules could
secrete potassium, and secretion was strongly implicated even when potassium excretion was
only a modest fraction of the filtered load. Early clearance studies also provided evidence for the
presently accepted model of potassium excretion, according to which most of filtered potassium
is reabsorbed in proximal nephron segments and potassium excretion in the urine depends on
controlled secretion in the distal nephron (7, 8, 97, 98). Moreover, clearance studies also
supported the view that potassium excretion was dependent on the availability of sodium in the
urine. Factors such as adrenal hormones, systemic acid-base changes, diuretics, and potassium
adaptation were shown to modulate potassium excretion by changes in the rate at which
potassium was secreted by the renal tubules (7, 8).
 View inline
 View popup
Table 1.
Approaches to the study of renal potassium excretion
With the revival of single-nephron studies in the 1950s, it became possible to localize the sites of
potassium transport along the nephron directly and to gain further insight into the factors
controlling potassium transport (86-90). It is interesting that the main conclusions about the
localization and mechanisms of potassium transport derived from clearance studies were fully
supported by micropuncture studies. Perfusion of tubules in vitro provided a refinement of
single-nephron studies by providing information on potassium transport in those nephron
segments not accessible to puncture (elements of the loop of Henle and collecting ducts). Such
studies also allowed much more extensive manipulations of the intra- and extratubular
environment and thus of luminal and peritubular factors controlling potassium transport (14, 42).
The application of electrophysiological methods in various nephron segments has been

invaluable for defining the driving forces for potassium transport across the apical and
basolateral cell membranes, as well as through paracellular pathways. Such studies, combined
with measurements of intracellular potassium ion activities, made possible the precise
localization of potassium transporters (ion pumps and ion channels) and thus the study of the
mechanisms by which physiological or pathophysiological events alter potassium transport (37,
40, 130). Most recently, patch-clamp techniques have made it possible to define the properties of
single potassium channels in both apical and basolateral membranes of tubule cells (38, 41, 103).
Morphological studies have also contributed significantly to our understanding of renal

potassium transport. Structure-function relations have supported the thesis that principal tubule
cells secrete whereas intercalated cells reabsorb potassium by demonstrating cell-specific
morphological changes of ultrastructure following potassium deprivation or potassium excess
(63-65, 83,128-130, 132-134). The combination of electron probe techniques with morphological
studies has also been useful, because it allows measuring the ion content of single tubule cells in
different states of transport. Rapid uptake of rubidium (a marker for potassium) occurs only into
principal but not intercalated cells (3, 4). Application of immunochemical analysis of ATPase
activity in single cells of the distal nephron fully supports the conclusion that principal but not
intercalated cells are involved in sodium reabsorption and potassium secretion (109).
Biochemical studies on single collecting ducts have been essential for defining several types of
ATPases in nephron segments that transport potassium. Relevant are studies on the adaptation of
both Na-K- and K-H-ATPases in single tubules and the activation of specific pump isoforms in
physiological and pathophysiological conditions (19-22, 36, 71, 171).
Finally, the advent of molecular biological techniques has further advanced our knowledge of the
structure of several proteins that mediate potassium transport. Molecules such as Na-K- and K-
H-ATPase as well as several renal potassium channels have been cloned (see Ref.120) and have
aided in the in-depth characterization of potassium transport.
Potassium Transport Along the Nephron

Studies on single tubules show that potassium excretion is mediated by three processes:
glomerular filtration, reabsorption along the proximal tubule and the loop of Henle, and
bidirectional transport (secretion and reabsorption) in the initial and cortical collecting tubule
(Fig.2). Potassium secretion was also demonstrated in isolated perfused collecting ducts in vitro
(14, 28,42, 106, 116, 117, 135).
 Download figure
 Open in new tab
Fig. 2.
Summary of potassium transport along the nephron. Following filtration, potassium is

extensively reabsorbed along the proximal tubule and the loop of Henle. Potassium is secreted
along the initial and cortical collecting tubule. Net secretion can be replaced by net reabsorption
in states of potassium depletion. Also shown are the two cell types lining the distal tubule and
cortical collecting duct. PCT, proximal tubule; TAL, thick ascending limb; CCT, cortical
collecting tubule; DCT, distal convoluted tubule; S, secretion; R, reabsorption; ALDO,
aldosterone; ADH, antidiuretic hormone; MCD, medullary collecting duct; ICT, initial
connecting tubule. [Reprinted from Giebisch and Wang (41).]
Figure 2 shows that regulated secretion (in principal tubule cells) is the source of potassium
excretion when potassium intake is normal or high, but potassium reabsorption (in intercalated
cells) may replace secretion when reduced potassium intake requires a very low level of urinary
excretion (37, 39-41, 86-90, 104, 173).
Cell Mechanisms of Potassium Transport
The direction and magnitude of potassium transport in the several nephron segments depend on
the site-specific distribution of transporters in the membranes of tubule cells. Potassium
movement may involve either transcellular or intercellular pathways. Figure3 illustrates the
mechanisms of potassium transport at four sites along the nephron. The transporters in the
basolateral membrane are generally similar; different transport mechanisms mediate potassium
movement in the apical membrane (41, 86,88, 130).
 Download figure
 Open in new tab
Fig. 3.
Cell models of potassium transport along the nephron. Note similarity of transporters in the
basolateral membrane and different transporters in the apical membrane. [Reprinted from
Giebisch and Wang (41).]
Proximal tubule. Micropuncture and microperfusion of proximal tubules have provided the
following picture of potassium reabsorption. First, the concentration of potassium varies little
along the proximal tubule, and fractional rates of reabsorption are similar to those of sodium and
water (37, 40, 86). Second, the transepithelial voltage is lumen negative in early loops and lumen
positive further down the proximal tubule (35). Third, net potassium movement is strongly
affected by sodium and water movement so that changes in fluid and potassium transport are
closely coupled (11).
Two mechanisms, solvent drag and diffusion, have been suggested as the major driving forces
for potassium reabsorption. Recent measurements of low reflection coefficients of potassium in
perfused proximal convoluted tubule in vivo strongly suggest that solvent drag is an important
driving force for potassium reabsorption (11, 165, 166) and that potassium ions, entrained in
tubule fluid, are reabsorbed largely along the paracellular pathway. However, the observation
that barium in the tubule fluid significantly lengthens the time of dissipation of imposed
transepithelial potassium gradients suggests participation of a transcellular route of proximal
potassium reabsorption by an unknown mechanism (147). Perfusion studies with several
transport inhibitors in vivo have not provided evidence for an active component of potassium
reabsorption (169).
The fact that the lumen of a large part of the proximal tubule is electrically positive with respect
to the peritubular fluid (35) provides a significant driving force for passive potassium
reabsorption. Lowering of the potassium concentration in the interspace has also been suggested
as an additional mechanism for potassium reabsorption by diffusion across the tight junction
(166).
Urinary excretion of potassium is not directly controlled by changes in its reabsorption along the
proximal tubule. However, secondary flow-dependent alterations in potassium transport along
distal nephron segments occur when sodium delivery increases (40, 41, 68, 84, 85).
Administration of mannitol, inhibition of reabsorption, high delivery rates of glucose, or reduced
transport of bicarbonate (carbonic anhydrase inhibitors) are relevant examples. Distal potassium
secretion may be suppressed when excessive reabsorption of sodium along the proximal tubule
lowers distal sodium and fluid delivery (130).
Loop of Henle. This nephron segment includes several anatomically and functionally distinct
nephron segments: the proximal straight tubule, the thin descending and ascending limbs, and the
thick ascending limb. Thin segments are absent in cortical loops. Knowledge of potassium
transport is based on both micropuncture of the tip of Henle’s loop and on microperfusion of
isolated perfused loop segments (61, 138, 139). The picture that has emerged suggests passive
secretory entry of potassium into the medullary segment of the proximal straight tubule and the
descending thin limb of Henle, as well as outward movement in the thin ascending limb. Both
processes occur by diffusion, favored by the high potassium permeability and appropriate
concentration gradients. Potassium entry into the thin descending limb is driven by the increasing
potassium concentration along the corticomedullary axis. Conversely, as the potassium
concentration in the interstitium declines toward the corticomedullary junction, potassium ions
are passively reabsorbed. Passive potassium entry into the descending limb of Henle is part of
the pathway of potassium recycling from medullary collecting ducts into the loop of Henle (62).
The mechanism of transport of potassium along the thick ascending limb of the loop in mammals
(40, 45, 46, 54) and the diluting segment of amphibians (49) is different from that in thin limbs.
Potassium is reabsorbed under physiological conditions, but secretion has also been observed
(39, 96, 142). Features of potassium reabsorption include two transport steps: apical uptake by
secondary active, electroneutral Na-2Cl-K cotransport and passive exit across the basolateral
membrane by diffusion through potassium channels or cotransport with Cl or HCO3 (43, 77,
130). A significant fraction of potassium reabsorption also passes through the paracellular
pathway driven by the lumen-positive transepithelial potential difference (122). Apical
potassium uptake is against a modest chemical gradient and depends on coupling to sodium that
enters the cell along a large electrochemical gradient generated by the basolateral Na-K-ATPase
activity.
A potassium conductance in the apical membrane is an essential component of potassium

transport; it also maintains the activity of the Na-2Cl-K cotransporter (9, 43-46, 53, 54, 152,
164). Potassium reabsorption may be replaced by potassium secretion when the Na-2Cl-K
cotransporter is inhibited, for instance, by loop diuretics (39, 96). Such reversal of the direction
of potassium movement is best explained by diffusion from cell to lumen along a favorable
electrochemical gradient, unopposed by cotransport-dependent potassium reabsorption.
Potassium recycling across the apical membrane is required for the normal activity of the Na-
2Cl-K cotransporter, because it provides an adequate supply of potassium ions. Removal of
potassium from the lumen or inhibition of the apical potassium conductance leads to a sharp
decline of sodium chloride reabsorption (43, 45, 49, 53, 54, 150, 151). The apical potassium
conductance is also essential for the generation of the lumen-positive potential difference, which
provides a significant driving force for passive cation reabsorption along the paracellular
transport pathway.
Of the known factors that regulate potassium transport in the thick ascending limb of Henle’s
loop, a low-potassium diet (141, 142), aldosterone, and vasopressin stimulate potassium
reabsorption (47, 53,127, 172), whereas potassium reabsorption is reduced by loop diuretics (43,
54, 58, 96), a high potassium intake (141, 142), and high plasma calcium (160). Arachidonic acid
lowers potassium channel activity and would thus be expected to reduce potassium reabsorption
(159). Prostaglandins are also involved in regulating Na-2Cl-K reabsorption, as demonstrated by
the attenuation of the diuretic response to loop diuretics when prostaglandin synthesis is
inhibited and reversal of this effect by placing prostaglandin E2 (69, 70) in the lumen.
Initial and cortical collecting tubule. Regulated secretion of potassium in the initial and cortical
collecting tubule plays a major role in urinary potassium excretion, but when potassium
conservation is required, reabsorption can replace secretion (104, 130, 173).
Potassium secretion occurs in principal cells by active uptake across the basolateral membrane
by Na-K-ATPase and passive diffusion across the apical membrane into the lumen (37, 40, 41,
86-90, 130). Besides diffusion along a favorable electrochemical gradient through potassium
channels, it has been suggested that there is electroneutral cotransport of potassium with chloride
in the apical membrane (12,25-27, 41, 130, 143, 144). The cell model in Fig. 3 also includes
apical sodium channels that permit sodium to enter principal cells passively and to depolarize the
apical membrane. High concentrations of sodium in the lumen thus favor the electrochemical
driving force for potassium diffusion into the lumen. Conversely, low concentrations of sodium
curtail potassium secretion by producing hyperpolarization of the apical membrane which
inhibits potassium secretion. The sodium channel blocker amiloride reduces potassium excretion
by a similar mechanism (24, 36). In addition to its effect on the apical membrane potential,
sodium affects potassium secretion by the requirement of the basolateral Na-K-ATPase for
sodium. Enhanced delivery of sodium into principal cells increases the intracellular sodium
concentration and stimulates basolateral sodium/potassium exchange. Accelerated potassium
uptake favors its diffusion across the apical membrane .
The strong dependence of potassium secretion on distal sodium supply explains the observation
that an increase in the delivery of sodium-containing fluid to the distal tubule increases
potassium secretion (24, 39, 68, 84, 85, 130). Figure4 shows that potassium secretion along the
distal tubule rises in a flow-dependent manner and that the effect is modified by the dietary
potassium intake. Figure 4 further shows that potassium secretion continues to increase, over the
physiological range of flow into the distal tubule. Accordingly, the secretory process is flow-
limited.
 Download figure
 Open in new tab
Fig. 4.
Relation between distal tubule flow rate and potassium secretion in animals on different
potassium-containing diets. Solid bar on abscissa indicates the physiological range of flow rates
into the early distal tubule of rats. [Modified from Malnic et al. (85).]
Tubule flow rate and sodium delivery thus play a major role in modulating potassium excretion.
Relevant examples include osmotic diuretics, reduction of proximal sodium chloride
reabsorption by extracellular volume expansion, or inhibition of sodium transport by diuretics
(carbonic anhydrase inhibitors, loop diuretics or thiazide diuretics). Common to all of these is
their site of action upstream of the initial and cortical collecting tubule (130). Tubule flow rate
and sodium delivery thus emerge as important determinants of distal potassium secretion.
It is virtually certain that changes in sodium intake have their effect on potassium excretion by
changing distal flow rate and sodium delivery (77). This has been shown in experiments
summarized in Fig.5 A in which the relationship between plasma potassium concentration and
potassium excretion was studied as a function of sodium intake. It is apparent that increasing
sodium intake has a stimulating effect on potassium excretion; accordingly, potassium balance is
achieved at lower plasma potassium concentrations as sodium intake rises. It should be noted
that hypokalemia decreases the stimulating effect of increasing sodium intake on potassium
excretion. This is consistent with the results of distal microperfusion studies (Fig. 4) showing
that flow-dependent stimulation of potassium secretion is reduced in hypokalemic animals (68,
85, 86).
 Download figure
 Open in new tab
Fig. 5.
A: relation between steady-state plasma potassium concentration and urinary potassium excretion
in the dog as a function of dietary sodium intake (in meq/day). Dogs were adrenalectomized and
given a fixed dose of aldosterone, and potassium content was varied at different sodium intake.
(See Ref. 177.)B: relation between steady-state plasma potassium concentration and urinary
potassium excretion as a function of aldosterone. Animals were adrenalectomized and given
fixed doses of aldosterone, and potassium content of the diet was varied. [Reprinted from Zhoa
et al. (178).]
It is also well established that mineralocorticoids stimulate potassium secretion in principal cells
(72, 99-103, 105, 106). A number of studies of the acute and chronic effects of these hormones
have shown that there is an increase in the turnover rate of the basolateral Na-K-ATPase,
insertion of new Na-K-ATPase units, and increases of permeability to both sodium and
potassium in the apical membrane (111,145, 146). In addition, the simultaneous increase in
electrogenic Na-K-ATPase activity associated with an increase in basolateral potassium
permeability induces a marked hyperpolarization of the cell potential with negativities
significantly in excess of −100 mV (72, 113). These electrical effects lead to a reversal of the
driving force for passive potassium transport across the basolateral membrane. As shown in Fig.
6, potassium ions in mineralocorticoid-treated animals now diffuse from peritubular fluid into
the cytoplasm because the membrane potential exceeds the potassium equilibrium potential (72,
113). Increased potassium uptake thus takes place not only by accelerated active uptake via Na-
K-ATPase but also passively through potassium conductive pathways (38, 72, 113).
 Download figure
 Open in new tab
Fig. 6.
Schema of cortical collecting tubule cell with key sites of potassium transport. Depending on the
magnitude of the electrical potential difference across the basolateral cell membrane, potassium
ions may either leave the cell (recycle, A) or be taken up into the cell in parallel with pump-
mediated potassium transport (B). [Modified from Giebisch (38).]
Figure 5 B demonstrates the role of aldosterone on potassium excretion (176). Stimulation by

aldosterone results in an increase of the slope of the relation between plasma potassium and
urinary potassium excretion. As a result, urinary excretion, as well as potassium balance, is
maintained at progressively lower plasma potassium concentrations as circulating aldosterone
levels rise (176).
The dependence of potassium secretion on sodium and flow poses problems, because obligatory
coupling of potassium excretion to distal flow rate and sodium delivery could jeopardize
potassium balance when flow rate into the distal tubule and collecting ducts changes
independently of potassium balance. Figure7 summarizes likely events that stabilize potassium
excretion during changes in extracellular fluid volume despite fluctuations in distal flow rate
(130). A fall in extracellular volume leads to increased reabsorption of sodium and fluid in the
proximal tubule and would thus decrease distal potassium secretion because of the delivery of
fluid and sodium to principal tubule cells declines. Potassium secretion should fall as a
consequence of diminished sodium and fluid delivery. However, the contraction in extracellular
volume also activates release of aldosterone, which stimulates distal potassium secretion.
Therefore, changes in potassium excretion are minimized. As a consequence of these opposing
effects, potassium excretion remains relatively constant. It is also known that potassium
excretion remains fairly stable during changes in flow rate that result from variations in
circulating vasopressin levels (130). It is reasonable to explain such stability of renal potassium
excretion by postulating that the stimulating effect of enhanced distal delivery of fluid and
sodium is offset by the fall in vasopressin, a hormone known to stimulate potassium secretion
(30, 32, 117).
 Download figure
 Open in new tab
Fig. 7.
Effect of extracellular fluid volume (ECFV) contraction on potassium secretion. Changes in
potassium secretion may be minimized because of opposing actions of aldosterone and tubule
flow rate on potassium secretion. [Reprinted from Stanton and Giebisch (130).]
The situation is different when potassium balance is threatened by the synergy of factors that
stimulate potassium secretion in principal tubule cells (130). Figure 8 illustrates the mechanisms
responsible for the kaliuretic effects of many diuretics. Most diuretic agents promote an increase
in sodium and fluid delivery to the distal tubule. At the same time, aldosterone release is
activated as the extracellular fluid volume shrinks with the loss of sodium, with both factors
acting synergistically to promote potassium secretion and kaliuresis. Similar increases of
potassium secretion may occur in hyperkalemia with an increase in dietary potassium intake,
when high flow rate due to inhibition of proximal sodium reabsorption and increased aldosterone
act synergistically to promote kaliuresis. Enhanced potassium excretion may also occur in
metabolic alkalosis when large amounts of bicarbonate reach the distal tubule fluid.
 Download figure
 Open in new tab
Fig. 8.
Effect of diuretics acting upstream of the initial collecting tubule on potassium secretion.
Potassium secretion is stimulated by the synergistic effects of high urine flow rate and high
aldosterone.
Potassium Reabsorption
The kidney’s ability for potassium reabsorption in distal nephron segments was suggested by
early observations that the concentration of potassium in the urine may fall below that in
surrounding medullary structures. Microperfusion studies have confirmed net reabsorption of
potassium along the perfused distal tubule in hypokalemic rats (104). Potassium reabsorption has
been localized to the intercalated cells in the initial and cortical collecting tubule (63, 65, 83,
130,132-134) and to cells of the collecting duct in the inner stripe of the outer medulla (170). It
has been proposed that there is a component of potassium reabsorption in the initial collecting
duct even during net secretion, because in microperfused tubules the steady-state transepithelial
concentration gradients of potassium were always below that expected from the electrical
potential difference (37, 40, 86, 87,130). Accordingly, net secretion may be the result of
simultaneous bidirectional secretory and reabsorptive potassium fluxes.
The discovery of potassium-activated ATPases in isolated collecting ducts has greatly advanced
our knowledge of the molecular mechanisms of potassium reabsorption. Several isoforms of H-
K-ATPases have been identified and shown to reabsorb potassium in exchange for hydrogen
ions; they share some functional properties with gastric and colonic ATPases (13, 20-23, 71, 170,
171). Both functional (123-125) and morphological evidence (83, 128, 129) suggest that β-
intercalated cells are an important, although perhaps not the exclusive, site of
potassium/hydrogen exchangers. There are morphological changes in intercalated cells such as
an increase in apical surface area and insertion of rod-shaped particles into the apical membrane
in hypokalemia and in metabolic acidosis, both conditions in which potassium reabsorption and
hydrogen ion secretion are increased (63,65, 83, 128). These morphological changes suggest that
potassium depletion induces recruitment of vesicles that contain potassium-absorbing transport
ATPases from a subapical pool and their insertion into the apical membrane (129). Upregulation
of this transport protein has been observed in potassium depletion (13,20-23, 71, 171), and
functional studies indicate stimulation by K+-H+pump activity during metabolic acidosis (113,
114) and sodium deprivation (115).
Renal Potassium Channels
Two methods have greatly enhanced our understanding of the mechanisms of renal potassium
transport. First, the introduction by Neher and Sakmann (103) of the patch-clamp technique has
made it possible to study the localization and the properties of potassium channels along the
nephron (38, 158, 162). Second, the cloning of renal potassium channels has provided new
insights into the structure of potassium channels and their regulation. Table 2 and Fig. 9
summarize the role of potassium channels in renal electrolyte transport (38).
 View inline
 View popup
Table 2.
Function of renal potassium channels

 Download figure
 Open in new tab
Fig. 9.
Localization of ATP-sensitive potassium channels along the mammalian nephron. [Reprinted

from Wang et al. (158).]
First, potassium channels are essential for generation of the cell-negative potential. A high
concentration of potassium is maintained in the cytoplasm of tubule cells by the energy-
dependent activity of the basolateral Na-K-ATPase (41, 130). Potassium channels provide a
potassium conductance in the basolateral membrane and are thus responsible for the generation
of the cell-negative diffusion potential, which provides an important driving force for the entry
of positively charged ions and cotransporters across the apical membrane of tubule cells (41).
Second, the regulation of the volume of renal tubule cells is strongly dependent on the activity of
potassium channels in both apical and basolateral membranes (38, 112, 130). Renal tubule cells
share with many body cells the ability to reduce their volume when swelling occurs as a result of
entry of solutes or dilution of their extracellular environment. Such volume regulatory decreases
depend on the activation of potassium channels (66, 67, 112). Activation of potassium channels,
with a simultaneous increase of anion conductance, allows potassium ions to leave the cell along
a favorable electrochemical gradient and to restore cell volume toward its initial set point.
Stretch-activated potassium channels are found in all nephron segments, but their mode of
activation differs: direct activation by membrane stretch or indirect activation by an increase in
the concentration of cell calcium resulting from stimulation of cation-selective channels (112).
The latter mechanism is present in apical membranes of proximal tubule cells and involves large-
conductance, calcium-activated potassium channels. These channels are also stimulated by
membrane depolarization (66, 67, 112).
Third, potassium recycling across the apical membrane of the thick ascending limb of Henle’s
loop, as well as through the basolateral membrane of tubule cells, depends on several subtypes of
potassium channels. Apical potassium channels in the thick ascending limb are important for the
regulated supply of potassium to the Na-2Cl-K cotransporter and the generation of the lumen-
positive potential, as demonstrated by the inhibition of sodium chloride absorption by blockers of
potassium channels (43-45, 158, 162). Potassium channels in the basolateral membrane allow
recycling and maintain an adequate supply of potassium in fluid compartments between cells for
the operation of the Na-K-ATPase across the basolateral membrane (17).
Finally, potassium channels in the apical membrane of principal cells in the initial and cortical
collecting duct mediate potassium secretion from cell to lumen (130). These channels, by
responding to a wide variety of regulatory stimuli, play a major role in determining potassium
secretion (38, 41, 130, 153).
Proximal tubule. Sensitivity to ATP, stretch, and pH are important features of potassium
channels in the basolateral membrane of proximal tubule cells (5, 6,44, 66, 67, 75, 91, 91, 95,
167). Potassium channels in the basolateral membrane are inhibited by millimolar concentrations
of Mg-ATP (5, 6) and by acidification of the cytosol (67, 95) and activated by cell swelling and
application of negative pressure to excised membrane patches (112). Several studies have
provided evidence that the ATP-sensitive potassium channels in the basolateral membrane of
proximal tubule cells link the potassium conductance to the activity of the Na-K-ATPase (5, 6,
140, 167; see below). Acidosis inhibits potassium channels in the basolateral membrane, an
effect consistent with the decrease of the potassium conductance in acidosis (75).
Thick ascending limb of the loop of Henle. Figure 10summarizes our present knowledge of the
factors that regulate potassium channel activity in the cells of the thick ascending limb (9, 44,
152, 158, 162, 164). Two channels with high open probability and conductances of 30 and 70 pS
are located in the apical membrane and are subject to regulation by changes in pH and the
concentrations of ATP, protein kinase A (PKA) and protein kinase C (PKC) (152). In addition, a
large-conductance potassium channel, not shown in Fig. 10, activated by calcium and membrane
depolarization, has been observed in cultured thick ascending limb cells (48). Because it has a
low open probability, it is unlikely to contribute importantly to the apical potassium
conductance; it may be activated by cell swelling and thus play a role in cell volume regulation.
 Download figure
 Open in new tab
Fig. 10.
Regulation of potassium channels in the apical membrane of cells in the thick ascending limb of
Henle (TAL); PKC, protein kinase C; PKA, protein kinase A; AA, arachidonic acid. [Reprinted
Changes in cell calcium concentration modulate both types of apical potassium channel
indirectly by activating PKC (160). The apical potassium channels are also inhibited by acidic
pH and millimolar concentrations of ATP. cAMP and PKA mediate vasopressin-induced
enhancement of channel activity. These results account for the previous observation that
vasopressin increases the apical potassium conductance. Such PKA-induced activation of apical
potassium channels increases sodium chloride reabsorption by enhancement of potassium
recycling across the apical membrane (52, 53).
Figure 10 shows that arachidonic acid is also an inhibitor of apical potassium channels, an effect
mediated by the cytochromeP-450 metabolite 20-HETE (159). The inhibition of apical
potassium channels that follows activation of basolateral calcium receptors has been found to be
an effect of this arachidonic acid metabolite (160), and it has been suggested thatP-450
metabolites thus link changes in extracellular calcium to apical sodium chloride reabsorption by
modulating recycling of potassium.
Cortical collecting tubule. Figure11 illustrates the factors that regulate the apical and basolateral
potassium channels (158). Two types of apical potassium channels have been found in rat and
rabbit principal tubule cells: not included in Fig. 11 is a large single-conductance potassium
channel with low open probability. This channel is activated by increase of cell calcium and by
membrane depolarization and is inhibited by tetraethylammonium (33, 59, 153,158). Its low
open probability makes it unlikely that it plays a role in potassium secretion, although it may be
involved in cell volume regulation.
 Download figure
 Open in new tab
Fig. 11.
Top: regulation of apical secretory potassium channel in principal tubule cells of the cortical
collecting tubule (CCD).Bottom: regulation of basolateral potassium channels in principal tubule
cells; CaMK II, calcium-calmodulin-dependent kinase II; PP, protein phosphatase. [Reprinted
There is now general agreement that a low-conductance, inwardly rectifying potassium channel
with high open probability mediates potassium secretion across the apical membrane of principal
cells in the initial and cortical collecting tubule (34, 38, 41, 52, 79, 108,119, 153, 158, 162). In
contrast to the large-conductance channel, the low-conductance channel has a significant
rubidium conductance (108), consistent with the observed secretion of rubidium by perfused
cortical collecting tubules (116). The low-conductance potassium channel has a high open
probability in physiological conditions of normal potassium intake. Recruitment of additional
channels increases apical potassium conductance in response to such factors as vasopressin, cell
alkalinization, or adaptation to high potassium intake (15, 107, 153,163). It is of interest that an
increase in potassium intake and aldosterone have separate but additive effects on enhancement
of apical potassium channel density (107). The apical potassium channel is highly sensitive to
acidification of the cytosol, and channel activity declines markedly when cell pH is reduced from
7.4 to 7.0 (16, 28,163). This is consistent with the effects of metabolic acidosis, which decreases
potassium secretion in distal tubules (130).
An important property of apical secretory potassium channels is their sensitivity to changes in

ATP. Patch-clamp studies have shown that low concentrations of ATP (in the submillimolar
range) are required for phosphorylation and for activation of channels, whereas millimolar
concentrations of ATP inhibit channel activity (156, 158, 163). ATP-induced channel inhibition
can be attenuated by ADP, cAMP-dependent PKA, and by an increase in pH. Secretory
potassium channels are stimulated by vasopressin as evidenced by patch-clamp studies that show
involvement of cAMP via a PKA-dependent pathway (15). These results are consistent with
observations in perfused distal tubules in vivo and cortical collecting ducts in vitro in which
vasopressin stimulated potassium secretion (32, 117).
The apical potassium channel is indirectly inhibited by raising intracellular calcium

concentrations (153, 156, 163). This effect can be demonstrated in cell-attached membranes
when the calcium concentration of principal cells is artificially increased. In contrast, exposure
of inside-out patches to high cytosolic calcium does not change channel activity (163). Several
lines of evidence suggest that PKC and calcium-calmodulin-dependent kinases are stimulated by
calcium and are involved in channel inhibition (73, 74). Conditions known to lower apical
potassium channel activity and potassium secretion, such as inhibition of basolateral Na-K-
ATPase activity (156; see below) or cyclosporin (78), involve calcium-induced changes in PKC
activity. Other factors that modulate apical potassium channels also include direct inhibition by
arachidonic acid (155) and interaction with the cytoskeleton (154).
The rapid decrease of channel activity that often follows membrane excision (channel “run-
down”) can be delayed or abolished by deletion of Mg or by phosphatase inhibitors (73). This
suggests that the balance between phosphorylation and dephosphorylation processes alters apical
potassium channel activity. The demonstrated presence of Mg-dependent and -independent
membrane-bound phosphatases is in accord with this inference (73).
Figure 11 also includes information on the regulation of basolateral potassium channels (158).
The technical problems of studying the basolateral membrane have been resolved by selective
removal of intercalated cells so as to expose lateral membranes of principal cells, or by
collagenase treatment (119, 158). Several channels with differing single channel conductance
have been identified (55, 80, 81,118, 119, 151, 158). Of special interest is their sensitivity to
inhibition by cell acidification and their stimulation by NO and cGMP (55, 151). Other features
of these channels are lack of inhibition by ATP and direct blockade by high cell calcium
(55,151).
Several lines of evidence indicate that NO is involved in the regulation of ion transport in
principal cells. First, it is inferred that NO stimulates basolateral potassium channels, because
inhibition of nitric oxide synthase reduces channel activity, whereas NO donors or cGMP
stimulate channels (151). Second, NO-induced cGMP formation hyperpolarizes the membrane
potential and secondarily augments apical sodium entry (81). On the other hand, the sodium
channel blocker amiloride downregulates basolateral potassium channels by a mechanism
involving changes in cell calcium and NO (80). Reduction of apical sodium entry and a fall in
cell sodium decreases calcium by stimulating basolateral Na+/Ca2+exchange. Since the synthesis
of NO is Ca2+ dependent, a fall in NO and cGMP reduces basolateral potassium channel activity.
Active sodium extrusion across the basolateral membrane and apical and basolateral potassium
channels are linked by two mechanisms (41) summarized in Figs. 12 and 13. Such relations are
important because they prevent disturbances in cell volume and cell ion content when there are
changes in net sodium reabsorption (51, 76, 121, 156).
 Download figure
 Open in new tab
Fig. 12.
Cell model including mechanisms that couple sodium transport and basolateral Na-K-ATPase
activity to basolateral K channels.Left: several Na-entry mechanisms in the apical membrane of
tubule cells. PT, proximal tubule; S, substrates like glucose, amino acids, etc. ATP-related
regulation of basolateral K channels following transport changes by Na-glucose cotransport has
been observed in isolated rabbit tubules. Transport-related changes in apical K channel activity
in the TAL and CCT could also be mediated by alterations in cell ATP. [Reprinted from
Giebisch and Wang (41).]
First, transport-induced changes in cell ATP concentrations regulate basolateral ATP-sensitive
potassium channels in proximal tubule cells (5, 6, 41, 60, 140, 156). Direct measurements of cell
ATP indicate that stimulation of basolateral Na-K-ATPase lowers ATP; pump inhibition has the
opposite effect. Measurements of basolateral membrane potentials and of potassium channel
activity in perfused proximal tubules show that upregulation of ATPase activity, achieved by
adding glucose or amino acids to the lumen, increases potassium channel activity. In contrast,
pump inhibition, because it reduces ATP consumption and increases cell ATP, closes channels.
Such coupling between Na-K-ATPase and basolateral potassium channels has been demonstrated
in proximal tubule cells (167) but, as indicated in Fig. 12, may also operate in the thick
ascending limb or in cortical collecting ducts. A similar mechanism could also link basolateral
Na-K-ATPase activity and apical secretory potassium channels, because these channels are
inhibited by ATP and could respond to transport-related alterations in cell ATP.
A second mechanism, shown in Fig. 13, involves transport-related changes in cell calcium (41,
156). In the illustrative example, the effects of inhibiting basolateral Na-K-ATPase increases cell
sodium and curtails extrusion of calcium by the basolateral Na/Ca exchange. The rise in cell
calcium that follows activates PKC, which blocks apical potassium channels. This calcium-
dependent coupling mechanism between basolateral Na-K-ATPase and apical potassium
channels involves changes in cell sodium. In contrast, pump-related alterations in consumption
of ATP may occur without change in cell sodium, if basolateral pump stimulation is matched by
increased sodium entry across the apical membrane.
 Download figure
 Open in new tab
Fig. 13.
Cell model including mechanisms that couple sodium transport and basolateral Na-K-ATPase
activity to apical K channels. Downregulation of apical K channels following inhibition of
basolateral Na-K-ATPase activity involving changes in cell Ca and PKC have been observed in
isolated rat CCT. It is likely that CaMK kinase II is also involved. [Reprinted from Giebisch and
Wang (41).]
It should be noted that additional mechanisms may relate basolateral pump activity with
potassium channels (Fig. 11). The observation that basolateral potassium channels are also
activated by membrane hyperpolarization (151) is consistent with the reported voltage
dependence of the basolateral membrane conductance in amphibian collecting ducts (57). In
view of the electrogenic nature of the basolateral Na-K pump, voltage-related conductance
changes provide an additional mechanism for coupling between Na-K-ATPase activity and
potassium channels.
Physiological coupling mechanisms between apical and basolateral transport. A striking

example of the complex interaction between apical and basolateral transporters in principal
tubule cells is the transport stimulation by aldosterone (1,30, 99, 107, 111, 145, 146). Typical of
that hormone response is the redundancy of mechanisms that control and correlate the activities
of the basolateral Na-K pump and apical sodium and potassium channels. Figure 14 provides a
summary of possible mechanisms. First, aldosterone rapidly stimulates Na-K-ATPase turnover in
the membrane; this is followed by delayed activation of genomic pump expression involving de
novo synthesis, targeting, and insertion of Na-K-ATPase molecules into the basolateral
membrane. Second, aldosterone augments the basolateral potassium permeability. Both of these
actions, electrogenic Na-K pump and potassium channel stimulation, increase the cell-negative
potential (72, 113, 115). A third effect of aldosterone is its stimulation of both sodium and
potassium channels in the apical membrane. Recruitment and insertion of Na-K-ATPase into the
basolateral membrane mediated by indirect mechanisms such as the increase in cell sodium have
also been reported (2). Some of the mechanisms discussed above, such as changes in cell
calcium, NO, and ATP, are likely mediators of the parallel activation of basolateral and apical
transport processes.
 Download figure
 Open in new tab
Fig. 14.
Summary of mechanisms involved in modulation of basolateral Na-K-AtPase by aldosterone

(A). Changes in Na-K-ATPase activity in basolateral membrane may be mediated by genomic
factors leading to alteration in pump synthesis, effects on pump turnover rate, substrate-related
effects of cell Na concentration by primary effects of aldosterone on apical Na channels, or
recruitment by cell Na concentration changes of latent pump units through exocytosis.
Additional factors may involve changes in basolateral K conductance (recycling of K and effects
of membrane voltage changes on electrogenic pump activity). Shown inbottom cell model is the
effect of changes in basolateral ATPase activity on apical K conductance. [Modified from Barlet-
Bas et al. (1).]
It should be emphasized that potassium secretion will be stimulated optimally only during
simultaneous upregulation of both potassium and sodium channels. If aldosterone were only to
increase opening of potassium channels, then the resulting increase of apical potassium
permeability would tend to hyperpolarize the apical membrane and reduce the electrochemical
driving force for passive potassium transport from cell to lumen (137). Stimuli of potassium
secretion such as aldosterone (90, 105, 114), a high-potassium diet under conditions of constant
aldosterone levels (101), and most likely metabolic alkalosis (131) increase both potassium and
sodium conductance in the apical membrane and thus prevent attenuation of the driving force for
potassium secretion .
Molecular Structure of Renal Potassium Channels
New insights into the mechanism of potassium secretion have been provided by cloning of
several potassium channels from renal tissue. They fall into several categories and include
isoforms of voltage- and cGMP-gated potassium channels, which share structural elements with
Shaker channels (15), and low-conductance, inwardly rectifying potassium channels (56, 168,
178). These channels are of interest because they share many properties with native potassium
channels in the apical membrane of cells in the thick ascending limb and in principal cells. No
information is yet available on the molecular structure of basolateral potassium channels and of
renal stretch- and Ca-activated channels.
Figure 15 shows the structural model of ROMK2 and includes the amino acid sequence of the
NH2 termini of alternatively spliced products of the ROMK gene (52, 56). This channel protein
has two membrane-spanning regions (M1 and M2) flanking an H5-like region, similar to the
channel pore of voltage-gated potassium channels. The alternatively spliced channel proteins
form functional channels and are differentially expressed along the nephron. ROMK2 is most
widely distributed (thick ascending limb and cortical collecting duct), ROMK1 is specifically
expressed in collecting ducts, and ROMK3 expression is limited to the medullary and cortical
thick ascending limb and distal convoluted tubule (10, 174). The question of heteromultimeric
complex formation is not resolved, but interactions of ROMK channels with the cystic fibrosis
transmembrane conductance regulator (CFTR) confer increased sensitivity to inhibition by
glibenclamide, a well-known potassium channel blocker, on the potassium channel, suggesting
subunit interactions (93).
 Download figure
 Open in new tab
Fig. 15.
Topology model (A) of ROMK2 and the amino acid sequences of the different NH2 termini of
the alternatively spliced products of the ROMK gene (B). InA, solid circles represent individual
amino acid residues, and the cylinders represent membrane-spanning helixes. Broken
circumscription in the COOH terminus surrounds the location of the PO4 binding loop or Walker
A site proposed to be involved in Mg-ATP binding. Potential protein kinase A (PKA) and
protein kinase C (PKC) phosphorylation sites, and the single N-glycosylation site (N-glycosyl)
are indicated. In B, amino acid sequences are shown by single letter codes; the asterisk indicates
potential PKC phosphorylation sites. [Modified from Hebert (52).]
ROMK channels share many properties with the low-conductance potassium channels in the
TAL and cortical collecting tubule. These include single channel conductance, weak inward Mg-
dependent rectification, cation selectivity, inhibitor sensitivity, inhibition by low internal pH and
by arachidonic acid. Loss of channel activity (“run-down”) is also observed in excised patches
and after treatment with protein phosphatases. The latter two effects can be reversed by cAMP
and low concentrations of ATP. Lack of sensitivity to external tetraethylammonium but
inhibition by higher concentrations of Mg-ATP have also been observed in ROMK2 (38, 41, 52,
158, 162). Site-directed mutagenesis experiments have identified specific amino acids that are
essential for pH sensitivity (16, 29), and three serine residues that mediate cAMP-mediated
phosphorylation have been identified (175). Any two of these phosphorylation sites are required
for channel activity and induce different kinetic modification of ROMK2 activity (82, 175).
Figure 15 also shows a region of the channel protein that contains a PO4 binding motif that was
shown to be involved in Mg-ATP binding and channel inhibition. Mutations in the COOH
terminus of the ROMK molecule have been identified in Bartter’s syndrome and are likely to
initiate loss of function of the channel molecule (94). Figure 16 is a model of the secretory
potassium channel molecule that includes factors known to regulate channel activity.
 Download figure
 Open in new tab
Fig. 16.
Structural model of ROMK channel protein with known factors modulating its activity. CaMKII;
PPtase, protein phosphatase; PKI, protein kinase inhibitor.
The challenge of future work will be to characterize further the behavior of potassium channels
in physiological and pathophysiological conditions, to investigate the interaction of messengers
with the channel protein, and to elucidate the way channels are synthesized and targeted to
specific membrane sites. It is hoped that cloning efforts will provide insights into the molecular
structure of potassium channels not yet identified, especially in the basolateral membrane. Such
reductionist approaches taken with a physiological perspective should advance our knowledge of
the mechanisms underlying renal potassium transport and its regulation.
Acknowledgments
I am especially indebted to R. W. Berliner, who has inspired much of my work on renal
potassium transport and who has provided guidance and advice over many years. I also very
much appreciate the editorial assistance of Leah Sanders.
Footnotes
 Figures 9-11 and 16 are reprinted with permission, from theAnnual Review of Physiology,
Volume 59 © 1997 by Annual Reviews.
 Work in my laboratory was supported by National Institute of Diabetes and Digestive and
Kidney Diseases Grant DK-17433.
 Copyright © 1998 the American Physiological Society
REFERENCES
1. ↵
1. Barlet-Bas C.,
2. Cheval L.,
3. Feraille E.,
4. Marsy S.,
5. Doucet A.
(1991) Regulation of tubular Na-K-ATPase. in Nephrology, Proceedings of the XIth

International Congress of Nephrology, ed Hatano M. (Springer, Berlin), pp 419–434.
Google Scholar
2. ↵
1. Barlet-Bas C.,
2. Khadouri C.,
3. Marsy S.,
4. Doucet A.
(1990) Enhanced intracellular sodium concentration in kidney cells recruits a latent pool
of Na-K-ATPase whose size is modulated by corticosteroids. J. Biol. Chem. 265:7799–
7803.
Abstract/FREE Full TextGoogle Scholar
3. ↵
1. Beck F. X.,
2. Dörge A.,
3. Blumner E.,
4. Giebisch G.,
5. Thurau K.
(1988) Cell rubidium uptake: a method for studying functional heterogeneity in the
nephron. Kidney Int. 33:642–651.
MedlineWeb of ScienceGoogle Scholar
4. ↵
Beck, F. X., and K. Thurau. Tracing the Na/K-ATPase with rubidium. Wien Klin.
Wochenschr. 109: 12–13: 424–428, 1997.
5. ↵
1. Beck J. S.,
2. Breton S.,
3. Mairbäurl H.,
4. Laprade R.,
5. Giebisch G.
(1991) The relationship between sodium transport and intracellular ATP in the isolated
perfused rabbit proximal convoluted tubule. Am. J. Physiol. 261(Renal Fluid Electrolyte
Physiol. 30):F634–F639.
6. ↵
1. Beck J. S.,
2. Hurst A. M.,
3. Lapointe J.-Y.,
4. Laprade R.
(1993) Regulation of basolateral K channels in proximal tubule studied during

continuous microperfusion. Am. J. Physiol. 264(Renal Fluid Electrolyte Physiol.
33):F496–F501.
7. ↵
1. Berliner R. W.
(1961) Renal mechanisms for potassium excretion. Harvey Lect. 55:141–171.
Google Scholar
8. ↵
1. Berliner R. W.,
2. Kennedy T. J. Jr..,
3. Hilton J. G.
(1950) Renal mechanisms for excretion of potassium. Am. J. Physiol. 162:348–367.
Google Scholar
9. ↵
1. Bleich M.,
2. Schlatter E.,
3. Greger R.
(1990) K+ channel of the thick ascending limb of Henle’s loop. Pflügers Arch. 415:449–
460.
CrossRefMedlineWeb of ScienceGoogle Scholar
10. ↵
1. Boim M. A.,
2. Ho K.,
3. Shuck M. E.,
4. Bienkowski M. J.,
5. Block J. H.,
6. Slightom J. L.,
7. Yang Y.,
8. Brenner B. M.,
9. Hebert S. C.
(1995) ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution
of alternative forms. Am. J. Physiol. 268(Renal Fluid Electrolyte Physiol. 37):F1132–
F1140.
11. ↵
1. Bomsztyk K.,
2. Wright F. S.
(1986) Dependence of ion fluxes on fluid transport by rat proximal tubule. Am. J.
Physiol. 250(Renal Fluid Electrolyte Physiol. 19):F680–F689.
Google Scholar
12. ↵
1. Brandis M.,
2. Keyes J.,
3. Windhager E. E.
(1972) Potassium-induced inhibition of proximal tubular fluid reabsorption in rats. Am.
J. Physiol. 222:421–427.
Google Scholar
13. ↵
1. Buffin-Meyer B.,
2. Younges-Ibrahim M.,
3. Barlet-Bas C.,
4. Cheval L.,
5. Marsy S.,
6. Doucet A.
(1997) K depletion modifies the properties of Sch-28080-sensitive K-ATPase in rat

collecting duct. Am. J. Physiol. 272(Renal Physiol. 41):F124–F131.
14. ↵
1. Burg M. B.
(1982) Introduction: background and development of microperfusion technique. Kidney

Int. 22:417–424.
15. ↵
1. Cassola A. C.,
2. Giebisch G.,
3. Wang W.
(1993) Vasopressin increases the density of apical low-conductance K channel in rat

CCD. Am. J. Physiol. 264(Renal Fluid Electrolyte Physiol. 33):F502–F509.
16. ↵
1. Choe H.,
2. Zhou H.,
3. Palmer L. G.,
4. Sackin H.
(1997) A conserved cytoplasmic region of ROMK modulates pH sensitivity, conductance,

and gating. Am. J. Physiol. 273(Renal Physiol. 42):F516–F529.
Google Scholar
17. ↵
1. Civan M. M.
(1981) Intracellular potassium in toad urinary bladder: the recycling hypothesis. in

Epithelial Ion and Water Transport, eds MacKnight A. D. C., Leader J. P. (Raven, New
York), p 107.
Google Scholar
18. ↵
1. Clausen T.
(1996) Long- and short-term regulation of the Na+,K+ pump in skeletal muscle. News
Physiol. Sci. 11:24–30.
19. ↵
1. Desir G. V.
(1995) Molecular characterization of voltage and cyclic nucleotide-gated potassium

channels in kidney. Kidney Int. 48:1031–1035.
20. ↵
1. DuBose T. D. Jr..,
2. Codina J.,
3. Burges A.,
4. Pressley T. A.
(1995) Regulation of H+-K+-ATPase expression in kidney. Am. J. Physiol. 269(Renal

Fluid Electrolyte Physiol. 38):F500–F507.
21. ↵
1. Doucet A.
(1997) H+,K+-ATPase in the kidney: localisation and function in the nephron. Exp.
Nephrol. 5:271–276.
22. ↵
1. Doucet A.,
2. Katz A. I.
(1980) Renal potassium adaptation: Na-K-ATPase activity along the nephron after
chronic potassium loading. Am. J. Physiol. 238(Renal Fluid Electrolyte Physiol.
7):F380–F386.
Google Scholar
23. ↵
1. Doucet A.,
2. Marsy S.
(1987) Characterization of K-ATPase activity in distal nephron: stimulation by potassium

depletion. Am. J. Physiol. 253(Renal Fluid Electrolyte Physiol. 22):F418–F423.
24. ↵
1. Duarte C.,
2. Chomety F.,
3. Giebisch G.
(1971) The effects of amiloride, ouabain and furosemide upon distal tubular function in
the rat. Am. J. Physiol. 221:632–640.
Google Scholar
25. ↵
1. Ellison D. H.,
2. Velázquez H.,
3. Wright F. S.
(1985) Stimulation of distal potassium secretion by low lumen chloride in the presence of
barium. Am. J. Physiol. 248(Renal Fluid Electrolyte Physiol. 17):F638–F649.
26. ↵
1. Ellison D. H.,
2. Velázquez H.,
3. Wright F. S.
(1986) Unidirectional potassium fluxes in the renal distal tubule: effects of chloride and
barium. Am. J. Physiol. 250(Renal Fluid Electrolyte Physiol. 19):F885–F894.
Google Scholar
27. ↵
1. Ellison D. H.,
2. Velázquez H.,
3. Wright F. S.
(1987) Mechanisms of sodium, potassium and chloride transport by the renal distal
tubule. Miner. Electrolyte Metab. 13:422–432.
28. ↵
1. Engbretson B. G.,
2. Stoner L. C.
(1987) Flow-dependent potassium secretion by rabbit cortical collecting tubule in vitro.

Am. J. Physiol. 253(Renal Fluid Electrolyte Physiol. 22):F896–F903.
29. ↵
1. Fakler B.,
2. Schultz J.,
3. Yang J.,
4. Schulte U.,
5. Bråandle U.,
6. Zenner H. P.,
7. Jan L. Y.,
8. Ruppersberg P.
(1996) Identification of a titratable lysine residue that determines sensitivity of kidney

potassium channels (ROMK) to intracellular pH. EMBO J. 15:4093–4099.
30. ↵
1. Field M. J.,
2. Giebisch G.
(1985) Hormonal control of renal potassium excretion. Kidney Int. 27:379–387.
31.
1. Field M. J.,
2. Stanton B. A.,
3. Giebisch G.
(1984) Differential acute effects of aldosterone, dexamethasone and hyperkalemia on
distal tubular potassium secretion in the rat kidney. J. Clin. Invest. 74:1792–1802.
Google Scholar
32. ↵
1. Field M. J.,
2. Stanton B. A.,
3. Giebisch G. H.
(1984) Influence of ADH on renal potassium handling: a micropuncture and

microperfusion study. Kidney Int. 25:502–511.
33. ↵
1. Frindt G.,
2. Palmer L. G.
(1987) Ca-activated K channels in apical membrane of mammalian CCT and their role in
K secretion. Am. J. Physiol. 252(Renal Fluid Electrolyte Physiol. 21):F458–F467.
34. ↵
1. Frindt G.,
2. Palmer L. G.
(1989) Low-conductance K channels in apical membrane of rat cortical collecting tubule.

35. ↵
1. Frömter E.,
2. Gessner K.
(1974) Free-flow potential profile along rat kidney proximal tubule. Pflügers Arch.
351:69–83.
36. ↵
1. Garg L. C.,
2. Narang N.
(1988) Ouabain-insensitive K-adenosine triphosphatase in distal nephron segments of the
rabbit. J. Clin. Invest. 81:1204–1208.
Google Scholar
37. ↵
1. Giebisch G.
(1979) Renal potassium transport. in Membrane Transport in Biology, eds Giebisch G.,
Tosteson D., Ussing H. H. (Springer Verlag, Heidelberg, Germany), pp 215–298.
Google Scholar
38. ↵
1. Giebisch G.
(1995) Renal potassium channels: an overview. Kidney Int. 48:1004–1009.
39. ↵
1. Giebisch G.,
2. Klein-Robbenhaar G.,
3. Klein-Robbenhaar J.,
4. Ratheiser K.,
5. Unwin R.
(1993) Renal and extrarenal sites of action of diuretics. Cardiovasc. Drugs Ther. 7:11–
21.
Google Scholar
40. ↵
1. Giebisch G. H.
(1987) Cell models of potassium transport in the renal tubule. in Current topics in
Membranes and Transport, ed Giebisch G. (Academic Press, Orlando, FL), 28:133–183.
Google Scholar
41. ↵
1. Giebisch G.,
2. Wang W.
(1996) Potassium transport: from clearance to channels and pumps. Kidney Int.
49:1624–1631.
42. ↵
1. Grantham J. J.,
2. Burg M. B.,
3. Orloff J.
(1970) The nature of transtubular Na and K transport in isolated rabbit collecting

tubules. J. Clin. Invest. 49:1815–1826.
Google Scholar
43. ↵
1. Greger R.
(1985) Ion transport mechanisms in thick ascending limb of Henle’s loop of mammalian
nephron. Physiol. Rev. 65:760–797.
FREE Full TextGoogle Scholar
44. ↵
1. Greger R.,
2. Gögelein H.
(1987) Role of K+ conductive pathways in the nephron. Kidney Int. 31:1055–1064.
45. ↵
1. Greger R.,
2. Schlatter E.
(1982) Presence of luminal K+, a prerequisite for active NaCl transport in the cortical
thick ascending limb of Henle’s loop of rabbit kidney. Pflügers Arch. 392:92–94.
Web of ScienceGoogle Scholar
46. ↵
1. Greger R.,
2. Weidtke C.,
3. Schlatter E.,
4. Wittner M.,
5. Gebler B.
(1984) Potassium activity in cells of isolated perfused cortical thick ascending limbs of
rabbit kidney. Pflügers Arch. 401:52–57.
47. ↵
1. Grossman E. B.,
2. Hebert S. C.
(1988) Modulation of Na-K-ATPase activity in thick ascending limb of Henle: effects of

mineralocorticoids and sodium. J. Clin. Invest. 81:885–892.
Google Scholar
48. ↵
1. Guggino S. E.,
2. Guggino W. B.,
3. Green N.,
4. Sacktor B.
(1987) Blocking agents of Ca2+-activated K+ channels in cultured medullary thick

ascending limb cells. Am. J. Physiol. 252(Cell Physiol. 21):C128–C137.
49. ↵
1. Guggino W. B.,
2. Oberleithner H.,
3. Giebisch G.
(1988) the amphibian diluting segment. Am. J. Physiol. 254(Renal Fluid Electrolyte
Physiol. 23):F615–F627.
50. ↵
1. Halperin M.,
2. Goldstein J.
(1994) Fluid, Electrolyte, and Acid-Base Physiology (Saunders, Philadelphia, PA), 2nd
ed. p 421.
51. ↵
1. Harvey B. J.
(1959) Cross-talk between sodium and potassium channels in tight epithelia. Kidney Int.
48:1191–1199.
CrossRefGoogle Scholar
52. ↵
1. Hebert S. C.
(1995) An ATP-regulated, inwardly rectifying potassium channel from rat kidney

(ROMK). Kidney Int. 48:1010–1016.
53. ↵
1. Hebert S. C.,
2. Andreoli T. E.
(1984) Effects of antidiuretic hormone on cellular conductive pathways in mouse

medullary thick ascending limbs of Henle. II. Determinants of the ADH-mediated
increase in transepithelial voltage and in net Cl absorption. J. Membr. Biol. 80:221–233.
54. ↵
1. Hebert S. C.,
2. Andreoli T. E.
(1984) Control of NaCl transport in the thick ascending limb. Am. J. Physiol. 246(Renal
55. ↵
1. Hirsch J.,
2. Schlatter E.
(1993) K+ channels in the basolateral membrane of rat cortical collecting duct. Pflügers
Arch. 424:470–477.
56. ↵
1. Ho K.,
2. Nichols C. G.,
3. Lederer W. J.,
4. Lytton J.,
5. Vassilev P. M.,
6. Kanazirska M. V.,
7. Hebert S. C.
(1993) cloning and expression of an inwardly rectifying ATP-regulated potassium
channel. Nature 362:31–38.
57. ↵
1. Horisberger J. D.,
2. Giebisch G.
(1988) Voltage dependence of the basolateral membrane conductance in the Amphiuma

collecting tubule. J. Membr. Biol. 105:257–263.
58. ↵
1. Hropot M.,
2. Fowler N.,
3. Karlmark B.,
4. Giebisch G.
(1985) Tubular action of diuretics: distal effects on electrolyte transport and

acidification. Kidney Int. 28:477–489.
59. ↵
1. Hunter M.,
2. Lopes A.,
3. Boulpaep E.,
4. Giebisch G.
(1986) Regulation of single K channels from apical membrane of rabbit collecting tubule.
60. ↵
1. Hurst A. M.,
2. Beck J. S.,
3. Laprade R.,
4. Lapointe J. Y.
(1993) Na pump inhibition downregulates an ATP-sensitive K channel in rabbit proximal

convoluted tubule. Am. J. Physiol. 264(Renal Fluid Electrolyte Physiol. 33):F760–F764.

61. ↵
1. Imai M.,
2. Taniguchi M.,
3. Tabei K.
(1987) Function of thin loops of Henle. Kidney Int. 31:565–579.
62. ↵
1. Jamison R. L.
(1987) Potassium recycling. Kidney Int. 31:695–703.
63. ↵
1. Kaissling B.
(1982) Structural aspects of adaptive changes in renal electrolyte excretion. Am. J.

Google Scholar
64. ↵
1. Kaissling B.,
2. Stanton B. A.
(1988) Adaptation of distal tubule and collecting duct to increased sodium delivery. I.
Ultrastructure. Am. J. Physiol. 255(Renal Fluid Electrolyte Physiol. 24):F1256–F1268.
65. ↵
1. Kaissling B.,
2. Stanton B. A.
(1985) Structure-function correlation in electrolyte transporting epithelia. in The Kidney:

Physiology and Pathophysiology, eds Seldin D. W., Giebisch G. H. (Raven, New York), p
707.
Google Scholar
66. ↵
1. Kawahara K.
(1990) A stretch-activated K channel in the basolateral membrane of Xenopus kidney
proximal tubule cells. Pflügers Arch. 415:624–629.
67. ↵
1. Kawahara K.,
2. Hunter M.,
3. Giebisch G.
(1987) Potassium channels in Necturus proximal tubule. Am. J. Physiol. 253(Renal Fluid
Electrolyte Physiol. 22):F488–F494.
68. ↵
1. Khuri R. N.,
2. Wiederholt M.,
3. Strieder N.,
4. Giebisch G.
(1975) Effects of flow rate and potassium intake on distal tubular potassium transfer. Am.
J. Physiol. 228:1249–1261.
Google Scholar
69. ↵
1. Kirchner K.
(1985) Prostaglandin inhibitors alter loop segment chloride uptake during furosemide
diuresis. Am. J. Physiol. 248(Renal Fluid Electrolyte Physiol. 17):F698–F704.
Google Scholar
70. ↵
1. Kirchner K.
(1987) Indomethacin antagonizes furosemide intratubular effects during loop segment

microperfusion. J. Pharmacol. Exp. Ther. 243:881–886.
71. ↵
1. Kone B. C.
(1996) Renal H,K-ATPase: structure, function and regulation. Miner. Electrolyte Metab.
22:349–365.
72. ↵
1. Koeppen B.,
2. Giebisch G.
(1985) Cellular electrophysiology of potassium transport in the mammalian cortical

collecting tubule. Pflügers Arch. 405:S143–S146.
Google Scholar
73. ↵
1. Kubokawa M.,
2. McNicholas C. M.,
3. Higgins M. A.,
4. Wang W-H.,
5. Giebisch G.
(1995) Regulation of renal ATP-sensitive K+ channel by membrane-bound protein

phosphatases in rat principal tubule cell. Am. J. Physiol. 269(Renal Fluid Electrolyte
Physiol. 38):F355–F362.
74. ↵
1. Kubokawa M.,
2. Wang W.,
4. Giebisch G.
(1995) Role of Ca2+/calmodulin-dependent protein kinase II in Ca2+-induced K+ channel

inhibition in rat CCD principal cell. Am. J. Physiol. 268(Renal Fluid Electrolyte Physiol.
37):F211–F219.
75. ↵
1. Kubota T.,
2. Biagi B. A.,
3. Giebisch G.
(1983) Effect of acid-base disturbances on basolateral membrane potential and
intracellular potassium activity in the proximal tubule of Necturus. J. Membr. Biol.
73:61–68.
76. ↵
1. Lapointe J.-Y.,
2. Barneau L.,
3. Bell P. D.,
4. Cardinal J.
(1990) Membrane crosstalk in the mammalian proximal tubule during alterations in

transepithelial sodium transport. Am. J. Physiol. 258(Renal Fluid Electrolyte Physiol.
27):F339–F345.
77. ↵
1. Leviel F.,
2. Borensztein P.,
3. Houillier P.,
4. Paillard M.,
5. Bichara M.
(1992) Electroneutral K+/HCO−3
 cotransport in cells of medullary thick ascending limb of rat kidney. J. Clin. Invest. 90:869–
878.
Google Scholar
 ↵
1. Ling B. N.,
2. Eaton D. C.
(1993) Cyclosporin A inhibits apical secretory K+ channels in rabbit cortical collecting tubule
principal cells. Kidney Int. 44:974–984.
 ↵
1. Ling B. N.,
2. Hinton C. F.,
3. Eaton D. C.
(1991) Potassium permeable channels in primary cultures of rabbit cortical collecting tubule.
Kidney Int. 40:441–452.
 ↵
1. Lu M.,
2. Giebisch G.,
3. Wang W.
(1997) Nitric oxide links the apical Na+ transport to the basolateral K+ conductance in rat CCD.
J. Gen. Physiol. 110:717–726.
 ↵
1. Lu M.,
2. Giebisch G.,
3. Wang W.
(1997) Nitric oxide-induced hyperpolarization stimulates low-conductance Na+ channel of rat

CCD. Am. J. Physiol. 272(Renal Physiol. 41):F498–F504.
 ↵
1. MacGregor G. G.,
2. Xu J. Z.,
4. Hebert S. C.,
5. Giebisch G.
(1997) Individual mutation of three PKA phosphorylation sites of ROMK2 (S25, S200 and S294)
decrease channel activity by different mechanisms (Abstract). J. Am. Soc. Nephrol. 8:39.
Google Scholar
 ↵
1. Madsen K. M.,
2. Tisher C. C.
(1986) Structural-functional relationships along the distal nephron. Am. J. Physiol. 250(Renal
 ↵
1. Malnic G.,
2. Berliner R. W.,
3. Giebisch G.
(1990) Transport stimulation by native tubule fluid. Am. J. Physiol. 258(Renal Fluid Electrolyte
Physiol. 27):F1523–F1527.
 ↵
1. Malnic G.,
2. Berliner R. W.,
3. Giebisch G.
(1989) Flow dependence of K secretion in cortical distal tubules of the rat. Am. J. Physiol.
256(Renal Fluid Electrolyte Physiol. 25):F932–F941.
 ↵
1. Malnic G.,
2. Klose R.,
3. Giebisch G.
(1964) Micropuncture study of renal potassium excretion in the rat. Am. J. Physiol. 206:674–
686.
Google Scholar
 ↵
1. Malnic G.,
2. Klose R.,
3. Giebisch G.
(1966) Microperfusion study of distal tubular potassium and sodium transfer in rat kidney. Am.
J. Physiol. 211:548–559.
Google Scholar
 ↵
1. Malnic G.,
2. Klose R. M.,
3. Giebisch G.
(1966) Micropuncture study of distal tubular potassium and sodium transport in rat nephron.
Am. J. Physiol. 211:529–547.
Google Scholar
 ↵
1. Malnic G.,
2. Mello-Aires M.,
3. Giebisch G.
(1971) Potassium transport across renal distal tubules during acid-base disturbances. Am. J.
Physiol. 221:1192–1208.
Google Scholar
 ↵
1. Marsh D. J.,
2. Ullrich K. J.,
3. Rumrich G.
(1963) Micropuncture analysis of the behavior of potassium ions in rat renal cortical tubules.
Pflügers Arch. 277:107–119.
CrossRefWeb of ScienceGoogle Scholar
 ↵
1. Mauerer U. R.,
2. Boulpaep E. L.,
3. Segal A. S.
(1998) Properties of an inwardly rectifying ATP-sensitive K+ channel on the basolateral

membrane of renal proximal tubule. J. Gen. Physiol. 111:139–160.
1.  Mauerer U. R.,
2. Boulpaep E. L.,
3. Segal A. S.
(1998) Regulation of an inwardly rectifying ATP-sensitive K+ channel on the basolateral

membrane of renal proximal tubule. J. Gen. Physiol. 111:161–180.
 ↵
2. Guggino W. B.,
3. Schwiebert E. M.,
4. Hebert S. C.,
5. Giebisch G.,
6. Egan M. E.
(1996) Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound,

glibenclamide, is enhanced by co-expression with the ATP-binding cassette transporter CFTR.
Proc. Natl. Acad. Sci. USA 93:8083–8088.
 ↵
2. Yang Y.,
3. Giebisch G.,
4. Hebert S. C.
(1996) Molecular site for nucleotide binding on an ATP-sensitive renal K+ channel (ROMK2).
 ↵
1. Merot J.,
2. Bidet M.,
3. Lemaout S.,
4. Tauc M.,
5. Poujeol P.
(1989) two types of K channel in the apical membrane of rabbit proximal tubule in primary
culture. Biochim. Biophys. Acta 978:134–144.
MedlineGoogle Scholar
 ↵
1. Morgan T.,
2. Tadokoro M.,
3. Martin D.,
4. Berliner R. W.
(1970) Effect of furosemide on Na+ and K+ transport studied by microperfusion of the rat
nephron. Am. J. Physiol. 218:292–297.
Google Scholar
 ↵
1. Mudge G. H.,
2. Foulks J.,
3. Gilman A.
(1948) The renal excretion of potassium. Proc. Soc. Exp. Biol. Med. 67:545–547.
 ↵
1. Mudge G. H.,
2. Foulks J.,
3. Gilman A.
(1950) Renal excretion of potassium in the dog during cellular dehydration. Am. J. Physiol.
161:159–166.
Google Scholar
 ↵
1. Muto S.
(1995) Action of aldosterone on renal collecting tubule cells. Curr. Opin. Nephrol. Hypertens.
4:31–40.
CrossRefMedlineGoogle Scholar
 ↵
1. Muto S.,
2. Giebisch G.,
3. Sansom S.
(1987) Effects of adrenalectomy on CCD: evidence for differential response of two cell types.
 ↵
1. Muto S.,
2. Sansom S.,
3. Giebisch G.
(1988) Effects of high K diet on the electrical properties of cortical collecting ducts from
adrenalectomized rabbits. J. Clin. Invest. 81:376–380.
Google Scholar
 ↵
1. Muto S.,
2. Yasoshima K.,
3. Yoshitomi K.,
4. Imai M.,
5. Asano Y.
(1990) Electrophysiological identification of α- and β-intercalated cells along the rabbit distal
nephron segments: effects of inhibitor. Exp. Nephrol. 1:301–308.
Google Scholar
 ↵
1. Neher E.,
2. Sakmann B.
(1976) Single channel currents recorded from membrane of denervated frog muscle fibers.
Nature 260:779–802.
Google Scholar
 ↵
1. Okusa M. D.,
2. Unwin R. J.,
3. Velázquez H.,
4. Giebisch G.,
5. Wright F. S.
(1992) Active potassium absorption by the renal distal tubule. Am. J. Physiol. 262(Renal Fluid
Electrolyte Physiol. 31):F488–F493.
 ↵
1. O’Neil R. G.
(1990) Aldosterone regulation of sodium and potassium transport in the cortical collecting
tubule. Semin. Nephrol. 10:365–374.
 ↵
1. O’Neil R. G.,
2. Helman S. I.
(1977) transport characteristics of renal collecting tubules: influences of DOCA and diet. Am. J.
 ↵
1. Palmer L. G.,
2. Antonian L.,
3. Frindt G.
(1994) Regulation of apical K and Na channels and Na/K pumps in rat cortical collecting tubule
by dietary K. J. Gen. Physiol. 104:693–710.
 ↵
1. Palmer L. G.,
2. Choe H.,
3. Frindt G.
(1997) Is the secretory K channel in the rat CCT ROMK? Am. J. Physiol. 273(Renal Physiol.
42):F404–F410.
 ↵
1. Ridderstrale Y.,
2. Kashgarian M.,
3. Koeppen B.,
4. Giebisch G.,
5. Stetson D.,
6. Ardito T.,
7. Stanton B.
(1988) Morphological heterogeneity of the rabbit collecting duct. Kidney Int. 34:655–670.
 ↵
1. Rosa R. M.,
2. Williams M. E.,
3. Epstein F. H.
(1985) Extrarenal potassium metabolism. in The Kidney: Physiology and Pathophysiology, eds
Seldin D. W., Giebisch G. H. (Raven, New York), p 2165.
Google Scholar
 ↵
1. Rossier B. C.,
2. Palmer L. G.
(1985) Mechanisms of aldosterone action on sodium and potassium transport. in The Kidney:
Physiology and Pathophysiology, eds Seldin D. W., Giebisch G. H. (Raven, New York), p 1373.
Google Scholar
 ↵
1. Sackin H.
(1995) Mechanosensitive channels. Annu. Rev. Physiol. 57:333–353.

 ↵
1. Sansom S. C.,
2. Agulian S.,
3. Muto S.,
4. Illig V.,
5. Giebisch G.
(1989) K activity of CCD principal cells from normal and DOCA-treated rabbits. Am. J. Physiol.
 ↵
1. Sansom S. C.,
2. O’Neil R. G.
(1985) Mineralocorticoid regulation of apical cell membrane Na+ and K+ transport of the
cortical collecting duct. Am. J. Physiol. 248(Renal Fluid Electrolyte Physiol. 17):F858–F868.
 ↵
1. Sansom S. C.,
2. O’Neil R. G.
(1986) Effects of mineralocorticoids on transport properties of cortical collecting duct

basolateral membrane. Am. J. Physiol. 251(Renal Fluid Electrolyte Physiol. 20):F743–F757.
 ↵
1. Schafer J. A.,
2. Troutman S. L.
(1987) Potassium transport in cortical collecting tubules from mineralocorticoid-treated rat.

 ↵
1. Schafer J. A.,
2. Troutman S. L.,
3. Schlatter E.
(1990) Vasopressin and mineralocorticoid increase apical membrane driving force for K
secretion in rat CCD. Am. J. Physiol. 258(Renal Fluid Electrolyte Physiol. 27):F199–F210.
 ↵
1. Schlatter E.,
2. Haxelmans S.,
3. Ankorina I.
(1996) Correlation between intracellular activities of Ca2+ and Na+ in rat cortical collecting
duct: a possible coupling mechanism between Na+-K+-ATPase and basolateral K conductance.
Kidney Blood Press. Res. 19:24–31.
 ↵
1. Schlatter E.,
2. Lohrmann E.,
3. Greger R.
(1992) Properties of the potassium conductances of principal cells of rat cortical collecting
ducts. Pflügers Arch. 420:39–45.
 ↵
1. Schlöndorff D.,
2. Bonventre J. V.
, eds (1995) Molecular Nephrology. (Dekker, New York).

 ↵
1. Schultz S. G.
(1981) Holeocellular regulatory mechanisms in sodium-transporting epithelia: avoidance of

extinction by “flush-through.” Am. J. Physiol. 241(Renal Fluid Electrolyte Physiol. 10):F579–
F590.
 ↵
1. Schwab A.,
2. Oberleithner H.
(1988) Trans- and paracellular K+ transport in diluting segment of frog kidney. Pflügers Arch.
411:268–272.
 ↵
1. Silver R. B.,
2. Frindt G.
(1993) Functional identification of H-K-ATPase in intercalated cells of cortical collecting

tubule. Am. J. Physiol. 264(Renal Fluid Electrolyte Physiol. 33):F259–F266.
 ↵
1. Silver R. B.,
2. Mennitt P.,
3. Satlin L.
(1996) Stimulation of apical H-K-ATPase in intercalated cells of cortical collecting duct with
chronic metabolic acidosis. Am. J. Physiol. 270(Renal Fluid Electrolyte Physiol. 39):F539–
F547.
 ↵
1. Silver R. B.,
2. Choe H. J.,
3. Frindt G.
(1997) Low NaCl diet induces H-K-ATPase in rat collecting duct (Abstract). J. Am. Soc.
Nephrol. 8:43.
Google Scholar
1.  Simon D. B.,
2. Karet F. E.,
3. Rodriguez-Soriano J.,
4. Hamdan J. H.,
5. DiPietro A.,
6. Trachtman H.,
7. Sanjad S. A.,
8. Lifton R. P.
(1996) Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel,

ROMK. Nat. Genet. 14:152–156.
 ↵
1. Stanton B.
(1986) Regulation by adrenal corticosteroids of sodium and potassium transport in loop of

Henle and distal tubule of rat kidney. J. Clin. Invest. 78:1612–1620.
Google Scholar
 ↵
1. Stanton B. A.
(1989) Renal potassium transport: morphological and functional adaptations. Am. J. Physiol.
257(Regulatory Integrative Comp. Physiol. 26):R989–R997.
 ↵
1. Stanton B. A.,
2. Biemesderfer D.,
3. Wade J. B.,
4. Giebisch G.
(1981) Structural and functional study of the rat distal nephron: effects of potassium adaptation
and depletion. Kidney Int. 19:36–48.
 ↵
1. Stanton B. A.,
2. Giebisch G.
Renal potassium transport.Handbook of Physiology: Renal Physiology1992Am. Physiol.

Soc.Bethesda, MD, sect. 8, vol. 1, chapt. 19, p. 813–874.
Google Scholar
 ↵
1. Stanton B.,
2. Giebisch G.
(1982) Effects of pH on potassium transport by renal distal tubule. Am. J. Physiol. 242(Renal
Google Scholar
 ↵
1. Stanton B.,
2. Janzen A.,
3. Wade J.,
4. DeFronzo R.,
5. Giebisch G.
(1985) Ultrastructure of rat initial collecting tubule: effect of adrenal corticosteroid treatment. J.
Clin. Invest. 75:1317–1326.
Google Scholar
 ↵
1. Stanton B.,
2. Kaissling B.
(1988) Adaptation of distal tubule and collecting duct to increased sodium delivery. II. Na+ and
K+ transport. Am. J. Physiol. 255(Renal Fluid Electrolyte Physiol. 24):F1269–F1275.
 ↵
1. Stetson D. L.,
2. Wade J. B.,
3. Giebisch G.
(1980) Morphological alterations in the rat medullary collecting duct following K depletion.
Kidney Int. 17:45–56.
 ↵
1. Stokes J. B.
(1981) Potassium secretion by cortical collecting tubule: relation to sodium absorption, luminal
sodium concentration, and transepithelial voltage. Am. J. Physiol. 241(Renal Fluid Electrolyte
Physiol. 10):F395–F402.
1.  Stoner L. C.,
2. Burg M. B.,
3. Orloff J.
(1974) Ion transport in cortical collecting tubule: effect of amiloride. Am. J. Physiol. 227:453–
459.
Google Scholar
 ↵
1. Strieter J.,
2. Weinstein A. M.,
3. Giebisch G. H.,
4. Stephenson J. L.
(1992) Regulation of K transport in a mathematical model of the cortical collecting tubule. Am.
J. Physiol. 263(Renal Fluid Electrolyte Physiol. 32):F1076–F1086.
 ↵
1. Tabei K.,
2. Imai M.
(1987) K transport in upper portion of descending limbs of long-loop nephron from hamster. Am.
J. Physiol. 252(Renal Fluid Electrolyte Physiol. 21):F387–F392.
 ↵
1. Tabei K.,
2. Imai M.
(1988) Potassium transport in the upper portion of descending limbs of Henle’s loop of long-
loop nephron isolated from hamster kidney. Am. J. Physiol. 254(Renal Fluid Electrolyte Physiol.
23):F438–F445.
Google Scholar
 ↵
1. Tsuchiya K.,
2. Wang W.,
3. Giebisch G.,
4. Welling P. A.
(1992) ATP is a coupling-modulator of parallel Na/K ATPase-K channel activity in the renal
proximal tubule. Proc. Natl. Acad. Sci. USA 89:6418–6422.
 ↵
1. Unwin R.,
2. Capasso G.,
3. Giebisch G.
(1994) Potassium and sodium transport along the loop of Henle: effects of altered dietary
potassium intake. Kidney Int. 46:1092–1099.
 ↵
1. Unwin R. J.,
2. Capasso G.,
3. Giebisch G.,
4. Shirley D. G.,
5. Walter S. J.
(1996) Loop of Henle (LOH) potassium transport and the urinary concentrating mechanism. in
Acid-Base and Electrolyte Balance, eds Desanto N. G., Capasso G. (Inst. Ital. Per gli Studi
Filosofici), II:243–256.
Google Scholar
 ↵
1. Velázquez H.,
2. Ellison D. H.,
3. Wright F. S.
(1987) Chloride-dependent potassium secretion in early and late renal distal tubules. Am. J.
 ↵
1. Velázquez H.,
2. Wright F. S.,
3. Good D. W.
(1982) Luminal influences on potassium secretion: chloride replacement with sulfate. Am. J.
 ↵
1. Verrey F.
(1995) Transcriptional control of sodium transport in tight epithelia by adrenal steroids. J.

Membr. Biol. 144:93–110.
 ↵
1. Verrey F.,
2. Beron J.,
3. Spindler B.
(1996) Corticosteroid regulation of renal Na,K-ATPase. Miner. Electrolyte Metab. 22:279–292.

 ↵
1. Vestri S.,
2. Malnic G.
(1990) Mechanism of potassium transport across proximal tubule epithelium in the rat. Braz. J.
Med. Biol. Res. 23:1195–1199.
1.  Wade J. B.,
2. O’Neil R. G.,
3. Pryor J. L.,
4. Boulpaep E. L.
(1979) Modulation of cell membrane area in renal cortical collecting tubules by corticosteroid
hormones. J. Cell Biol. 81:439–445.
1.  Wang T.,
2. Wang W-H.,
3. Klein-Robbenhaar J.,
4. Giebish G.
(1995) Effects of glyburide on renal tubule transport and K channel activity. Renal Physiol.
Biochem. 18:169–182.
 ↵
1. Wang T.,
2. Wang W-H.,
3. Klein-Robbenhaar G.,
4. Giebisch G.
(1995) Effects of a novel K ATP channel blocker on renal tubule function and K channel activity.
J. Exp. Pharmacol. Ther. 273:1382–1389.
 ↵
1. Wang W. H.
(1995) Regulation of the hyperpolarization-activated K channel in the lateral membrane of the
CCD. J. Gen. Physiol. 106:25–43.
 ↵
1. Wang W.
(1994) Two types of K+ channel in thick ascending limb of rat kidney. Am. J. Physiol. 267(Renal
 ↵
1. Wang W. H.
(1995) View of K+ secretion through the apical K channel of cortical collecting duct. Kidney Int.
48:1024–1030.
 ↵
1. Wang W-H.,
2. Cassola A.,
3. Giebisch G.
(1994) Involvement of actin cytoskeleton in modulation of apical K channel activity in rat

collecting duct. Am. J. Physiol. 267(Renal Fluid Electrolyte Physiol. 36):F592–F598.
 ↵
1. Wang W.,
2. Cassola A.,
3. Giebisch G.
(1992) Arachidonic acid inhibits the secretory K channel of cortical collecting duct of rat kidney.
 ↵
1. Wang W.,
2. Geibel J.,
3. Giebisch G.
(1993) Mechanism of apical K+ channel modulation in principal renal tubule cells: effect of
inhibition of basolateral Na+-K+-ATPase. J. Gen. Physiol. 101:673–694.
1.  Wang W.,
2. Giebisch G.
(1991) Dual effect of adenosine triphosphate on the apical small conductance K+ channel of the
rat cortical collecting duct. J. Gen. Physiol. 98:35–61.
 ↵
1. Wang W.,
2. Hebert S. C.,
3. Giebisch G.
(1997) Renal K channels: structure and function. Annu. Rev. Physiol. 59:413–416.
 ↵
1. Wang W. H.,
2. Lu M.
(1995) Effect of arachidonic acid on activity of the apical K channel in the thick ascending limb
of the rat kidney. J. Gen. Physiol. 106:727–743.
 ↵
1. Wang W. H.,
2. Lu M.,
3. Hebert S. C.
(1996) P450 metabolites mediate extracellular Ca2+-induced inhibition of apical K+ channels in

the thick ascending limb of the rat kidney. Am. J. Physiol. 270(Cell Physiol. 39):C103–C111.
Google Scholar
1.  Wang W.,
3. Segal A. S.,
4. Giebisch G.
(1994) A novel approach allows identification of K channels in the lateral membrane of rat
CCD. Am. J. Physiol. 266(Renal Fluid Electrolyte Physiol. 35):F813–F822.
 ↵
1. Wang W.,
2. Sackin H.,
3. Giebisch G.
(1992) Renal potassium channels and their regulation. Annu. Rev. Physiol. 54:81–96.
 ↵
1. Wang W.,
2. Schwab A.,
3. Giebisch G.
(1990) The regulation of the small conductance K+ channel in the apical membrane of rat
cortical collecting tubule. Am. J. Physiol. 259(Renal Fluid Electrolyte Physiol. 28):F494–F502.
 ↵
1. Wang W.,
2. White S.,
3. Geibel J.,
4. Giebisch G.
(1990) A potassium channel in the apical membrane of rabbit thick ascending limb of Henle’s
loop. Am. J. Physiol. 258(Renal Fluid Electrolyte Physiol. 27):F244–F253.
 ↵
1. Wareing M.,
2. Wilson R. W.,
3. Kibble J. D.,
4. Green R.
(1995) Estimated potassium reflection coefficient in perfused proximal convoluted tubules of the
anaesthetized rat in vivo. J. Physiol. (Lond.) 488:153–161.
 ↵
1. Weinstein A. M.
(1988) Modeling the proximal tubule: complications of the paracellular pathway. Am. J. Physiol.
 ↵
1. Welling P. A.
(1995) Cross-talk and the role of KATP channels in the proximal tubule. Kidney Int. 48:1017–
1023.
 ↵
1. Welling P. A.
(1997) Primary structure and functional expression of a cortical collecting duct Kir channel. Am.
J. Physiol. 273(Renal Physiol. 42):F825–F836.
Google Scholar
 ↵
1. Wilson R. W.,
2. Wareing M.,
3. Green R.
(1997) The role of active transport in potassium reabsorption in the proximal convoluted tubule
of the anaesthetized rat. J. Physiol. (Lond.) 500:155–164.
 ↵
1. Wingo C. S.
(1989) Active proton secretion and potassium reabsorption in the rabbit outer medullary
collecting duct. Functional evidence for proton-potassium-activated adenosine triphosphatase. J.
Clin. Invest. 84:361–365.
Google Scholar
 ↵
1. Wingo C. S.,
2. Cain B. D.
(1993) The renal H-K-ATPase: physiological significance and role in potassium homeostasis.
Annu. Rev. Physiol. 55:323–347.
 ↵
1. Work J.,
2. Jamison R. L.
(1987) Effect of adrenalectomy on transport in the rat medullary thick ascending limb. J. Clin.
Invest. 80:1160–1164.
Google Scholar
 ↵
1. Wright F. S.,
2. Giebisch G.
(1978) Renal potassium transport: contributions of individual nephron segments and

populations. Am. J. Physiol. 235(Renal Fluid Electrolyte Physiol. 4):F515–F527.
Google Scholar
 ↵
1. Xu J. Z.,
2. Hall A. E.,
3. Peterson L. N.,
4. Bienkowski M. J.,
5. Eessalu T. E.,
6. Hebert S. C.
(1997) Localization of the ROMK protein on apical membranes of rat kidney nephron segments.
Am. J. Physiol. 273(Renal Physiol. 42):F739–F748.
Google Scholar
 ↵
1. Xu Z-C.,
2. Yang Y.,
3. Hebert S. C.
(1996) Phosphorylation of the ATP-sensitive, inwardly rectifying K+ channel, ROMK, by cyclic

AMP-dependent protein kinase. J. Biol. Chem. 271:9313–9319.
 ↵
1. Young D. B.
(1988) Quantitative analysis of aldosterone’s role in potassium regulation. Am. J. Physiol.

 ↵
1. Young D. B.,
2. Jackson T. E.,
3. Tipayamontri U.,
4. Scott R. C.
(1984) Effects of sodium intake on steady-state potassium excretion. Am. J. Physiol. 246(Renal
Google Scholar
 ↵
1. Zhou H. S.,
2. Tate S.,
3. Palmer L. G.
(1994) Primary structure and functional properties of an epithelial K channel. Am. J. Physiol.
266(Cell Physiol. 35):C809–C824.

Renal

Hochgeladen von

Dokumentinformationen

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Renal

Hochgeladen von

Copyright:

Verfügbare Formate

Abstract

An understanding of potassium homeostasis requires considering the special distribution of

A: potassium homeostasis depends on maintenance of external and internal potassium balance.

Approaches to the Study of Renal Potassium Excretion

Approaches to the study of renal potassium excretion

The application of electrophysiological methods in various nephron segments has been

Morphological studies have also contributed significantly to our understanding of renal

Potassium Transport Along the Nephron

Summary of potassium transport along the nephron. Following filtration, potassium is

Cell Mechanisms of Potassium Transport

A potassium conductance in the apical membrane is an essential component of potassium

Figure 5 B demonstrates the role of aldosterone on potassium excretion (176). Stimulation by

Renal Potassium Channels

Function of renal potassium channels

Localization of ATP-sensitive potassium channels along the mammalian nephron. [Reprinted

An important property of apical secretory potassium channels is their sensitivity to changes in

The apical potassium channel is indirectly inhibited by raising intracellular calcium

Physiological coupling mechanisms between apical and basolateral transport. A striking

Summary of mechanisms involved in modulation of basolateral Na-K-AtPase by aldosterone

Molecular Structure of Renal Potassium Channels

 Copyright © 1998 the American Physiological Society

(1991) Regulation of tubular Na-K-ATPase. in Nephrology, Proceedings of the XIth

Abstract/FREE Full TextGoogle Scholar

MedlineWeb of ScienceGoogle Scholar

Abstract/FREE Full TextGoogle Scholar

(1993) Regulation of basolateral K channels in proximal tubule studied during

Abstract/FREE Full TextGoogle Scholar

(1961) Renal mechanisms for potassium excretion. Harvey Lect. 55:141–171.

CrossRefMedlineWeb of ScienceGoogle Scholar

Abstract/FREE Full TextGoogle Scholar

(1997) K depletion modifies the properties of Sch-28080-sensitive K-ATPase in rat

Abstract/FREE Full TextGoogle Scholar

(1982) Introduction: background and development of microperfusion technique. Kidney

MedlineWeb of ScienceGoogle Scholar

(1993) Vasopressin increases the density of apical low-conductance K channel in rat

Abstract/FREE Full TextGoogle Scholar

(1997) A conserved cytoplasmic region of ROMK modulates pH sensitivity, conductance,

(1981) Intracellular potassium in toad urinary bladder: the recycling hypothesis. in

Abstract/FREE Full TextGoogle Scholar

(1995) Molecular characterization of voltage and cyclic nucleotide-gated potassium

MedlineWeb of ScienceGoogle Scholar

(1995) Regulation of H+-K+-ATPase expression in kidney. Am. J. Physiol. 269(Renal

Abstract/FREE Full TextGoogle Scholar

MedlineWeb of ScienceGoogle Scholar

(1987) Characterization of K-ATPase activity in distal nephron: stimulation by potassium

Abstract/FREE Full TextGoogle Scholar

Abstract/FREE Full TextGoogle Scholar

MedlineWeb of ScienceGoogle Scholar

(1987) Flow-dependent potassium secretion by rabbit cortical collecting tubule in vitro.

Abstract/FREE Full TextGoogle Scholar

(1996) Identification of a titratable lysine residue that determines sensitivity of kidney

MedlineWeb of ScienceGoogle Scholar

(1985) Hormonal control of renal potassium excretion. Kidney Int. 27:379–387.

CrossRefMedlineWeb of ScienceGoogle Scholar

(1984) Influence of ADH on renal potassium handling: a micropuncture and

CrossRefMedlineWeb of ScienceGoogle Scholar

Abstract/FREE Full TextGoogle Scholar

(1989) Low-conductance K channels in apical membrane of rat cortical collecting tubule.

Abstract/FREE Full TextGoogle Scholar

CrossRefMedlineWeb of ScienceGoogle Scholar

(1995) Renal potassium channels: an overview. Kidney Int. 48:1004–1009.

CrossRefMedlineWeb of ScienceGoogle Scholar

(1970) The nature of transtubular Na and K transport in isolated rabbit collecting

FREE Full TextGoogle Scholar