Renal Division, Department of Medicine, and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322
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ABSTRACT |
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Research over the
past 25 years has identified specific ion transporters and channels
that are activated by acute changes in cell volume and that serve to
restore steady-state volume. The mechanism by which cells sense changes
in cell volume and activate the appropriate transporters remains a
mystery, but recent studies are providing important clues. A curious
aspect of volume regulation in mammalian cells is that it is often
absent or incomplete in anisosmotic media, whereas complete volume
regulation is observed with isosmotic shrinkage and swelling. The basis
for this may lie in an important role of intracellular
Cl in controlling
volume-regulatory transporters. This is physiologically relevant, since
the principal threat to cell volume in vivo is not changes in
extracellular osmolarity but rather changes in the cellular content of
osmotically active molecules. Volume-regulatory transporters are also
closely linked to cell growth and metabolism, producing requisite
changes in cell volume that may also signal subsequent growth and
metabolic events. Thus, despite the relatively constant osmolarity in
mammals, volume-regulatory transporters have important roles in
mammalian physiology.
cell volume; regulatory volume increase; regulatory volume decrease; sodium-potassium-chloride cotransporter; sodium-proton antiporter
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INTRODUCTION |
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THE NECESSITY TO RAPIDLY REGULATE volume
after shrinkage or swelling is obvious in cells from lower organisms,
which are continually exposed to osmotic stress. Yet, in mammals, where
osmolarity of the internal milieu is carefully regulated, cells also
exhibit rapid volume-regulatory responses. Are volume-regulatory
pathways in mammalian cells merely a vestige that have no significant
physiological role? The answer to this question lies in the realization
that mammalian cells are still subject to volume changes, despite a relatively constant osmolarity. This is most apparent in transporting epithelia, where slight changes in the large apical and basolateral fluxes could lead to rapid changes in cell volume. Furthermore, even if
cell volume were not threatened, mechanisms are still needed to alter
cell volume, such as during hypertrophy and atrophy, apoptosis, and
differentiation. Thus mammalian cells clearly require volume-regulatory
mechanisms, despite their isosmotic existence. Although the principal
volume-regulatory transporters have been identified and characterized,
their activation by changes in cell volume is poorly understood and
their physiological role is largely unexplored. This review focuses on
the salient points of volume-regulatory ion transporters that have
direct relevance to mammalian physiology, with particular emphasis on
the distinction between anisosmotic and isosmotic volume regulation,
the role of intracellular
Cl, and the need for cell
volume regulation in vivo. Space does not permit a detailed discussion
of the intracellular sensing and signaling mechanisms, and readers are
referred to a recent, comprehensive review on this subject (94).
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DETERMINANTS OF CELL VOLUME |
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In discussing cell volume it is important to distinguish between factors that determine steady-state volume and mechanisms that correct acute perturbations in steady-state volume. This has been a source of confusion, and it is best to consider these as entirely separate processes. Transporters responsible for correcting acute changes in cell volume are usually not active at steady-state volume. Thus steady-state cell volume is not a balance between their ongoing, opposing actions. Rather, cells appear to establish a steady-state volume and then activate volume-regulatory transporters only when cell volume deviates from this "set point." This is far more efficient than having opposing volume-regulatory transporters continuously active.
Steady-State Cell Volume
Mere existence in an isosmotic environment represents a continual threat to cell volume and integrity due to the large concentration of impermeant, negatively charged molecules within cells, such as proteins, nucleic acids, and other organophosphates. In addition to the osmotic force generated by the molecules themselves, there is an additional osmotic force due to an asymmetrical distribution of permeant ions created by the impermeant anions. Known as the Gibbs-Donnan equilibrium (65, 115), this is actually a steady-state disequilibrium. Unless the osmotic gradient is counterbalanced, there would be continuous influx of water and ions. In theory this counterbalancing could be accomplished by hydrostatic pressure, but it is highly unlikely that the plasma membrane can generate the tension required to balance the Donnan effect (115). In the absence of an opposing force, cells must either restrict permeability or actively extrude fluid. Because mammalian cells are generally quite permeable to water and there is no evidence for active transport of water, it must be solute that is actively transported and has restricted diffusion. This is illustrated by ionophores and other compounds that increase membrane permeability to Na+ and K+, which produce cell swelling without altering the Gibbs-Donnan "equilibrium." In addition, this confirms that membrane tension is not responsible for maintaining steady-state cell volume.Another simple maneuver that causes cell swelling is replacement of
extracellular Na+ with
K+. Because neither the
Gibbs-Donnan equilibrium nor other osmotic forces are altered (115),
elimination of the outward K+
gradient is directly implicated in cell swelling. By virtue of the
selective permeability of the plasma membrane to
K+ over
Na+, this gradient results in an
outward K+ current and a negative
membrane potential that dictates a low intracellular concentration of
permeant anions, primarily
Cl. The source of energy is
ultimately the
Na+-K+
pump, explaining why its inhibition often leads to cell swelling. This
ability to extrude Cl
(coupled with extrusion of Na+ by
the
Na+-K+
pump) appears to be the principal mechanism that maintains steady-state cell volume. In cells with high anion permeability and low membrane potential, such as erythrocytes, it is the net cation extrusion by the
Na+-K+
pump coupled with low membrane permeability to both
Na+ and
K+ that limits
Cl
entry. In erythrocytes
from carnivores, which lack
Na+-K+
pumps, net cation extrusion occurs through combined action of Ca2+ pumps
(Ca2+-ATPases) and
Na+/Ca2+
exchangers. The former generates a very large inward
Ca2+ gradient that is then used to
pump out Na+ via the latter (127).
Cl
accompanies
Na+ efflux by virtue of the
electrogenicity of both transporters.
Acute Changes in Steady-State Volume
The steady-state disequilibrium that maintains cell volume can be threatened by changes in extracellular osmolarity, but a far more common threat is a change in the cellular content of osmotically active molecules, so-called isosmotic volume change. Cell volume can be viewed as a balance between the osmotic effects of high concentrations of impermeant anions and low concentrations of ClCells instead recruit additional mechanisms to correct acute deviations
in their volume. These processes, termed regulatory volume increase
(RVI) and regulatory volume decrease (RVD), occur through activation of
specific transporters in the plasma membrane that mediate net fluxes of
osmotically active molecules (and therefore water). Not surprisingly,
both
[Cl]i
and macromolecule concentration play key roles in governing these
volume-regulatory responses. A further adaptation to osmotic stress is
the accumulation of organic osmolytes such as sorbitol, sn-glycero-3-phosphorylcholine,
betaine, and taurine, which occurs in response to increased ionic
strength rather than cell shrinkage (70, 207) and therefore is not
truly a volume-regulatory mechanism. Instead, these compounds replace
high intracellular salt concentrations that can perturb protein
structure and impair enzyme function (18, 70), enabling cells to
function in high osmolarity, such as in the renal medulla. Organic
osmolytes also appear in the brain during chronic hypernatremia and
comprise the so-called idiogenic osmoles (195). Organic osmolytes do
have an impact on volume regulation, because they must be rapidly
removed when normal osmolarity is restored in order to prevent cell swelling.
The mechanism by which cells sense changes in their volume is unknown but clearly is not through changes in osmolarity, ionic strength, or ion concentration, since isosmotic volume changes also activate RVI and RVD. Cell volume could be sensed chemically as changes in the intracellular concentration of impermeant molecules or mechanically through some form of stretch receptor. The former possibility, proposed by Minton et al. (129) and based on the concept of macromolecular crowding, is supported by direct experimental data. According to this theory, it is not cell volume per se that is regulated but rather the state of intracellular water. In erythrocytes, volume-regulatory transporters can be activated in the absence of changes in cell volume by altering intracellular protein concentration or by adding agents that perturb protein hydration (157). These findings have been extended to nonerythroid cells, specifically renal tubular cells (83) and barnacle muscle (200). The question that remains is the nature of the sensor for macromolecular crowding. Mechanical sensing of cell volume is an attractive theory, since cell structure is directly threatened, but the evidence is indirect. Agents that perturb the actin cytoskeleton can inhibit RVD (24, 25, 42, 49, 184), and channels activated directly by membrane stretch can also be activated by cell swelling (176). Mechanical sensing of changes in cell volume remains speculative since no role for the cytoskeleton has been demonstrated in RVI, and the role of stretch-activated channels in RVD remains unproven. The issue of how cells sense their volume is far from resolved, and it is quite possible that both chemical and mechanical sensors are employed.
Consequences of Cell Shrinkage and Swelling
What exactly are the detrimental effects of changes in cell volume that volume-regulatory mechanisms are designed to prevent? Aside from extreme results such as cell lysis, this is an area that has received little attention. The most obvious effects of changing cell volume are mechanical, since the function of many cells depends on their architecture. Close examination reveals blebbing of the plasma membrane after severe hypotonic swelling (217). In addition to direct distortion, shrinkage and swelling also induce rapid changes in the actin cytoskeleton (Ref. 66 and P. B. Perry and W. C. O'Neill, unpublished observations), presumably as a protective measure to ease tension on the plasma membrane. At the tissue level, swelling of parenchymal cells can compromise regional blood flow, possibly aggravated by swelling of vascular endothelium and smooth muscle (17). Due to its rigid confines, the brain is the predominant site of morbidity from hyponatremia and hypernatremia, and, accordingly, is the tissue that exhibits the most complete volume regulation. At the cellular level, swelling and shrinkage could alter metabolic reactions through changes in the concentrations of enzymes and substrates. In this regard, cell swelling is more of a problem than cell shrinkage, which is well tolerated. For instance, in alveolar macrophages, hypotonic swelling decreases O2 consumption and increases lactate production while there is little effect of hypertonic shrinkage (169). In mouse L cells, halving cell volume with extracellular sorbitol does not alter growth or the oxidation or metabolism of glucose (119). In both these studies and in other studies, severe hypertonic shrinkage (osmolarity >700 mosM) does impair cell growth and metabolism, but this appears to be an effect of increased ionic strength rather than cell shrinkage (18, 70). ![]() |
REGULATORY VOLUME INCREASE |
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Volume-Regulatory Transporters
A seemingly simple way for cells to increase volume after shrinkage is by the opening of Na+ channels, with Cl
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The mechanism by which cell shrinkage activates NKCC1 or NHE1 is unknown. Because activation occurs within minutes, it cannot be due to increased synthesis of transporters. Current data suggest that protein phosphorylation is involved. Activation of NKCC1 by shrinkage is associated with phosphorylation of the transporter (on serine and threonine, but not tyrosine) and can be blocked by kinase inhibitors and mimicked by inhibitors of protein phosphatases (90, 163). Although these agents have a similar effect on NHE1 activity (9), cell shrinkage does not increase phosphorylation of the transporter (53). The data imply the existence of a volume-sensitive protein kinase (or more than one) that phosphorylates NKCC1 and a regulatory protein that activates NHE1. Hopefully, the recent demonstration of a volume-sensitive kinase that phosphorylates NKCC1 in vitro will lead to identification of this kinase (145). Although the identity of this kinase is unknown, other volume-sensitive kinases have been tentatively identified. One of these is myosin light chain kinase (MLCK), which is activated by shrinkage in vascular endothelial and smooth muscle cells (89), mesangial cells (203), and glial cells (188). Inhibition of MLCK blocks activation of NKCC1 in shrunken endothelial cells (89) and activation of NHE1 in shrunken astrocytes (188). However, MLCK is not the volume-sensitive kinase that phosphorylates NKCC1, and the mechanism by which myosin light chain phosphorylation influences NKCC1 and NHE1 is unknown. Hypertonicity increases phosphorylation of stress-activated protein kinases and mitogen-activated protein (MAP) kinases (45, 69). It is not known whether this is an effect of hypertonicity or cell shrinkage, and phosphorylation of MAP kinase also occurs after hypotonicity, suggesting a nonspecific stress response rather than a specific response to cell volume. However, phosphorylation and activation of the tyrosine kinases p59fgr and p56/59hck occurred in neutrophils shrunken both hypertonically and isosmotically (91), directly implicating cell shrinkage.
Hypertonic vs. Isosmotic Shrinkage
It is important to distinguish between these two fundamentally different types of cell shrinkage because the response frequently differs, a fact that is often not appreciated. Hypertonic shrinkage removes only water from cells, whereas isosmotic shrinkage results from loss of osmotically active molecules, usually KCl. Examples of isosmotic shrinkage include returning cells to isotonic medium after volume regulation in hypotonic medium, substituting external Na+ or Cl
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Can thermodynamics explain the lack of hypertonic RVI? When
hypertonicity is produced with an impermeant molecule such as sucrose
or mannitol, the concentration of extracellular ions is unchanged while
intracellular ions increase in concentration, thereby reducing the
driving force for influx. This can actually lead to further cell
shrinkage (101) and is accentuated by the occasional use of impermeant
molecules in place of NaCl in the reference isotonic solution. However,
hypertonic RVI is still infrequent when NaCl is the osmotic agent.
Given reasonable estimates of intracellular ion activities, activation
of NKCC1 should result in net influx of ions, primarily because of the
inwardly directed Cl
gradient. In the absence of accurate determinations of intracellular ion activities, it can always be argued that NKCC1 is at equilibrium. However, substitution of external
Na+ with
K+ to equalize their
concentrations still does not result in net influx and RVI, despite the
fact that the driving force for influx is increased sevenfold (143,
168). Furthermore, thermodynamics cannot explain a lack of hypertonic
RVI by NHE1 and anion exchange, provided some
CO2 and
HCO
3 are present. These results
indicate that the lack of RVI in hypertonic medium is a regulatory
event rather than a thermodynamic effect. This could be because the
responses to the two types of shrinkage are inherently different (40)
or could be explained by superimposed regulatory effects of ionic
strength or intracellular ion concentrations. In either event it is
clear that cells can sense how they are being shrunk.
Although the difference between isosmotic and hypertonic shrinkage
could be sensed as a change in ionic strength or an agonist-induced signal, the most logical candidate is
[Cl]i.
Cl
is a minority anion in
most cells, yet it is the major permeant anion, with the majority of
anions being impermeant proteins and organophosphates. While hypertonic
shrinkage increases
[Cl
]i
in parallel with all other cytoplasmic constituents,
[Cl
]i
decreases with isosmotic shrinkage, since the fluid moving out of cells
has a higher Cl
concentration than cytoplasm. As with hypertonic shrinkage, the concentration of all other cytoplasmic constituents increases (except
for K+, which should change little
since it comprises the vast majority of intracellular cations). The
decrease in
[Cl
]i
is actually greater than the decrease in cell volume, making Cl
concentration a more
sensitive indicator of changes in cell volume than cell volume itself
under isosmotic conditions. As shown in Fig.
2, if
Cl
accounts for one third
of cellular anions and a cell loses one sixth of its volume via loss of
KCl, half the cell Cl
is
lost and
[Cl
]i
theoretically decreases by 40% (1/2 the original
Cl
content in 5/6 the
original volume). It is not surprising then that
[Cl
]i
has important effects on volume-regulatory transporters.
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[Cl]i
inhibits NKCC1, and this occurs through inhibition of phosphorylation
and probably through a direct effect on the transporter as well.
Phosphorylation of NKCC1 is stimulated by lowering
[Cl
]i
and inhibited by raising
[Cl
]i
(57, 111), probably via effects on the same kinase activated by cell
shrinkage (110). However, this cannot be the principal mechanism that
blocks hypertonic RVI, since there is still a substantial increase in
NKCC1 phosphorylation with hypertonic shrinkage, suggesting that
Cl
has an additional,
direct effect on NKCC1. The inhibition of NKCC1 by
Cl
in internally perfused
squid axons (16) is consistent with this hypothesis. In a sense this
represents classic feedback inhibition of NKCC1 and provides an ideal
yet simple mechanism for regulating cell volume. The nature of this
Cl
effect is unclear. In
endothelial cells, hypertonic and isosmotic shrinkage activate
unidirectional influx through NKCC1 to about the same degree, yet net
influx only occurs after the latter (143). This suggests that
intracellular Cl
blocks net
influx while allowing the partial reaction
[K+(Rb+)/K+
exchange] to continue. Evidence for inhibition of NKCC1 by
internal Cl
has also been
obtained in Ehrlich ascites cells (101), salivary acinar cells (168),
and tracheal epithelial cells (58). In many cells NKCC1 apparently
functions in a similar mode at steady-state volume as well (21, 46,
101, 116, 143, 150), essentially "running in neutral" due to
inhibition by intracellular
Cl
, yet poised for rapid
influx when
[Cl
]i
decreases. Because cells already expend energy to counteract swelling
due to the Gibbs-Donnan equlibrium, it makes little sense to allow net
influx via NKCC1 or NHE1 at steady-state volume.
The mechanism by which hypertonic shrinkage prevents RVI by NHE1 has
not been examined. In the absence of
CO2/HCO3, RVI could be limited by the alkalinization that accompanies
Na+ influx and rapidly shuts off
NHE1. For instance, if shrinkage produces a 0.2 unit alkaline shift in
the pH set point for NHE1 and the internal buffering capacity is 30 mM/pH unit, NHE1 shuts off after an influx of only 6 mM
Na+. The fact that more
substantial RVI via NHE1 can occur in the nominal absence of
CO2/HCO
3
(after isosmotic shrinkage) indicates that there is still enough
CO2/HCO
3 to permit some
Cl
/HCO
3
exchange. Because hypertonic RVI requires more
Na+ influx, it may be
substantially slower under these conditions. However, there appears to
be an additional mechanism since hypertonic shrinkage can actually
suppress activation of NHE1, presumably due to an effect of internal
Cl
(168).
Inhibition of RVI by intracellular
Cl may explain the variable
responses to hypertonic shrinkage noted in Table 1. Epithelial cells,
which frequently exhibit hypertonic RVI, may have a significantly lower
[Cl
]i
that is below the threshold for inhibition of RVI even after hypertonic
shrinkage. Some epithelia that do not exhibit RVI under standard
hypertonic conditions do so in the presence of agents that raise cAMP
levels (43, 54, 202), most likely via activation of
Cl
channels and reduction
of
[Cl
]i.
Hypertonic RVI by C6 glioma cells appears to require additives as well,
including insulin and PGE1 (133).
This could also be due to a decrease in
[Cl
]i,
but the possibility that these agents might modulate the inhibitory effect of Cl
cannot be
ruled out. An additional additive that confers hypertonic RVI on renal
epithelial cells is butyrate (135, 170). The mechanism is not known,
but the RVI is only partly accounted for by monovalent ions (170),
suggesting that butyrate stimulates the synthesis of organic osmolytes.
The occasional observation of hypertonic RVI in other cells and the
discrepancies between studies employing similar cells could be due to
subtle differences in culture conditions or the inadvertent presence of
agonists or growth factors, perhaps autocrine in nature.
Hypertonic RVI may also depend on the rate of shrinkage. In renal
proximal tubules, no shrinkage occurred when tonicity was increased 1.5 mosM/min, whereas the cells behaved as perfect osmometers at 3 mosM/min
(104). A similar response has been described in C6 glioma cells (134),
but these cells do exhibit some RVI after acute hypertonic shock (133).
The basis for this so-called isovolumetric regulation is unknown but
could relate to the fact that
[Cl
]i
is not markedly elevated during shrinkage. This phenomenon is probably
not widespread, since most tissues do not exhibit RVI during
hypertonicity in vivo, which also develops gradually.
Hypertonic Shrinkage In Vivo
The lack of RVI in most isolated or cultured cells is supported by data obtained in whole tissue and in vivo. During infusion of mannitol into dogs, the total intracellular water compartment behaves as a perfect osmometer (216), and in perfused skeletal muscle, which accounts for 75% of total intracellular water, there is no recovery of intracellular water after hypertonic shrinkage (68). A 6% increase in osmolarity in rats produced by dehydration decreased total intracellular water by 11% (137), with a decrease noted in muscle and several other tissues except brain. In dehydrated humans, loss of cellular water from skeletal muscle was precisely the inverse of the 7% increase in osmolarity (26), with no increase in the content of K+ or ClBased on both in vitro and in vivo data, it appears that mammalian cells are poised to undergo RVI after isosmotic shrinkage but not hypertonic shrinkage. This might seem appropriate since these cells reside in an environment of constant osmolarity. But is the osmolarity of mammalian plasma and interstitial fluid truly that constant? Despite the best efforts of the hypothalamus, kidneys, colon, and skin, significant water losses still occur during water deprivation. Thus osmolarity fluctuates with the frequency of water intake. In various rodents and ungulates, particularly those that reside in arid areas, water loss that exceeds 20% of body weight is well tolerated (112, 181). Deprivation for as short as 1 day can lead to a 6% or greater weight loss (112, 181). Some of this fluid comes from the intestinal lumen (113) and there is also excretion of electrolytes, so the corresponding rise in osmolarity is not as great. Deprivation of water increases plasma osmolarity 6-7% after 8 days in kangaroo rats (193), 4 days in dogs (224), and 3 days in Moroccan goats (76). In humans, strenuous exercise in hot conditions without water can result in water losses up to 5% of body weight (8% of total body water, 7% increase in osmolarity) without functional impairment (26, 100). Because periods of water deprivation are probably common in mammals, hypertonicity appears to be a routine occurrence that is well tolerated.
The lack of hypertonic RVI may instead be due to potential detrimental effects on the organism. Substantial water losses are often well tolerated, without circulatory collapse, because the loss is distributed across all compartments (intracellular, interstitial, and intravascular). If RVI occurred, the water loss would be concentrated in the one third of body water that is not intracellular. A 10% loss of body water would instead result in a 30% decrease in extracellular volume, including intravascular volume. Thus the absence of RVI helps maintain vascular volume during water deprivation, essentially allowing tissues to serve as a water reservoir (112). Another serious consequence of RVI would be the profound transcellular shift of K+. Correction of a mere 1% cell shrinkage via cellular uptake of KCl could decrease plasma K+ concentration as much as 3 mM.
Because of the potential detrimental effects of hypertonic RVI and the seemingly minimal detrimental effects of mild hypertonic shrinkage, RVI may be sacrificed for the benefit of the whole organism. Exceptions appear to be intestinal epithelium (138) and brain (3, 28, 29, 137, 192) and cells cultured from these sites (116, 133). Because intestinal epithelium is one of the few tissues routinely exposed to sudden changes in osmolarity, hypertonic RVI would be appropriate, particularly since cell shrinkage could disrupt the mucosal barrier. The brain is a critical organ with limited capacity to shrink without structural damage because of the inelasticity of the skull. Another exception may be chondrocytes. The extracellular fluid in cartilage is hypertonic compared with plasma, owing to the high concentration of fixed, polyanionic macromolecules, and this can change with applied load (64). Hypertonic RVI is occasionally observed in chondrocytes in situ but not in isolated chondrocytes (Ref. 63 and A. C. Hall, personal communication). The specific mechanism that allows hypertonic RVI to proceed in some tissues and cells but not in others is unknown.
Isosmotic Shrinkage In Vivo
It appears that volume-regulatory pathways in mammalian cells are designed with the dual purpose of avoiding RVI after hypertonic shrinkage yet mediating rapid volume recovery after isosmotic shrinkage. So when does the need for isosmotic RVI arise? Isosmotic shrinkage results from cellular loss of osmotically active molecules, usually K+ and Cl ![]() |
REGULATORY VOLUME DECREASE |
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Volume-Regulatory Transporters
The predominant pathway for RVD is the opening of K+ channels and anion channels. The K+ channels involved are usually large-conductance, Ca2+-activated channels (so-called BK channels). The molecular basis of the anion conductance is unknown and may comprise more than one channel (196). The conductance can be quite nonselective and can include a variety of organic anions in addition to ClAn additional transporter that mediates RVD is the
K+-Cl
cotransporter (KCC), which transports
K+ and
Cl
stoichiometrically in
either direction across the plasma membrane (98). Although structurally
related to NKCC1 and inhibited by furosemide, this transporter is
distinguished by its Na+
independence and insensitivity to bumetanide. Among physiological anions, it has a strict requirement for
Cl
and, not surprisingly,
is the principal mechanism for RVD in cells with a high
[Cl
]i
such as erythrocytes. Studies of KCC have been hampered by the lack of
a specific inhibitor, but, based on mRNA abundance, the transporter is
probably more prevalent than previously thought (47, 48, 132). For
instance, it appears to be responsible for about one-half the RVD in
aortic endothelial cells (160).
The mechanisms by which cell swelling activates volume-sensitive
channels and KCC are poorly understood. The nature of the K+ channels involved suggests
Ca2+ as a signal, and evidence in
support of this has been obtained primarily in epithelial cells (22,
31, 72, 121, 122, 172, 173, 189, 221). The hypothesis based on these
data is that cell swelling induces
Ca2+ influx, possibly via
stretch-activated channels, leading to a rise in
[Ca2+]i
and subsequent activation of BK channels. However, in many other cells
only a small rise in
[Ca2+]i
occurs and is not required for activation of
K+ efflux (52, 74, 125, 161, 222).
One possible explanation for this discrepancy is the distinction
between dependence on Ca2+ and
activation by Ca2+. The
K+ channels may require
Ca2+ for activity, but swelling
could open them through a separate mechanism. Maneuvers that block
increases in
[Ca2+]i
(such as removing extracellular
Ca2+) often lower basal
[Ca2+]i,
thereby preventing channel activation by any mechanism. Further evidence against the Ca2+ theory
is that Ca2+ is not involved in
the activation of anion channels or
K+-Cl
cotransport in swollen cells. Because the evidence for
Ca2+ signaling of RVD is quite
compelling in epithelial cells, it is reasonable to hypothesize two
pathways for activation of K+
channels by cell swelling: a mechanosensitive
Ca2+ influx that is the primary
pathway in epithelia and a
Ca2+-independent pathway
operational in nonepithelial cells. The nature of the
Ca2+-independent signal is
unknown, but phospholipase A2 has
been implicated in volume-sensitive
K+ and anion channels (136, 147),
whereas protein kinase inhibition has been implicated in the activation
of KCC in swollen erythrocytes (11, 82, 84). Unfortunately, it has not
yet been possible to determine whether the cotransporter itself is phosphorylated.
Hypotonic vs. Isosmotic Swelling
Essentially all cells (with the exception of some erythrocytes) respond to hypotonic swelling with an RVD, but the response is usually incomplete and cells remain swollen. The failure to complete RVD has remained a mystery, but recent studies in endothelial cells provide an explanation (Fig. 3). When these cells are swollen isosmotically by loading them with KCl, which raises [Cl
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Hypotonic Swelling In Vivo
Despite the fact that mammalian cells regulate their volume in hypotonic medium, the need rarely arises in vivo. At the level of the whole organism, hypotonicity can only occur from excess water intake (in the absence of pathological states), which is possible since thirst is not driven exclusively by osmolarity. For instance, mild hypotonicity will develop when water is provided to rats deprived of water for 10 h (182). As a localized phenomenon, hypotonicity may be more frequent. Ingestion of water can render the intestinal lumen hypotonic, and this can even extend to the liver since portal blood can become hypotonic after water ingestion (71). The RVD exhibited by isolated cells appears to accurately reflect the occurrence of RVD in vivo. In rats made hyponatremic through administration of water and vasopressin, total intracellular water increased far less than predicted and total body K+ decreased (208, 209), consistent with RVD. This is indicative of RVD in skeletal muscle, since it contains most of the cellular water, but hypotonic RVD has also been demonstrated in specific organs including liver (59, 96), heart (151), and brain (195).Isosmotic Swelling In Vivo
Isosmotic swelling is a much more common occurrence and results from an increase in the cellular content of osmotically active molecules. Examples include uptake of nutrients, acidosis, or depolarization of the cell membrane potential. Uptake of nutrients, particularly amino acids and sugars, can and must occur rapidly in tissues responsible for their assimilation after meals such as intestinal epithelium, liver, and skeletal muscle. In Ehrlich ascites cells, for instance, 10 mM glycine, a physiological postprandial concentration, produces a 17% increase in cell volume through Na+-coupled uptake (77), and a similar response has been noted in intact, perfused liver (71). Nutrient-induced swelling followed by RVD is also observed in mammalian intestine (117). RVD after nutrient uptake is incomplete, probably due to dilution of intracellular ClAcidosis can also increase cell volume, a response that is distinct and
opposite from the effect of pH on the Gibbs-Donnan equilibrium. By
titrating negative charges on impermeant molecules, a reduction in pH
decreases the tendency of cells to swell. However, this is more than
offset by accumulation of the anions that accompany the
H+ and replace impermeant anions
titrated by the H+ (79). If
intracellular buffering capacity is 30 mM/pH unit, lowering cell pH by
0.5 with a monovalent acid would lead to accumulation of 15 mM anion.
Cell swelling occurs during all three types of acidosis: organic,
inorganic, and respiratory. With organic acids such as lactic acid, the
anion accumulates not only within cells in which they are synthesized
but also in other cells, because the acids are weak and permeant and
because the anions can be transported (105). The resulting swelling has
been demonstrated in astrocytes (80, 81, 105) and erythrocytes (191).
Hydrochloric acidosis, the principal inorganic acidosis in vivo, can be
created in vitro by replacing HCO3
with Cl
. The assumption is
that HCO
3 leaves cells in exchange for
Cl
, transmitting the
acidosis to the cytoplasm. Because of intracellular buffering, the
amount of HCO
3 leaving the cell and
replacement anions entering will be greater than the drop in
HCO
3 concentration, leading to an
increase in osmotically active molecules. In renal proximal tubular
cells, a decrease in HCO
3
concentration from 25 to 5 mM increased cell volume by 6% (198), but
there was no accumulation of
Cl
(199), suggesting a
different counteranion. In respiratory acidosis CO2 diffuses into cells and
dissociates into H+, which are
buffered, and HCO
3, which accumulates and is partly exchanged for extracellular
Cl
. Accordingly, an
increase in CO2 from 5 to 15%
produced swelling of renal proximal tubules accompanied by an increase
in the cellular content of both HCO
3
and Cl
(199). An additional
mechanism of swelling in acidosis is activation of counterregulatory
pathways. In astrocytes exposed to organic acids, activation of NHE1 by
intracellular acidification leads to a second phase of swelling (80,
81). It is not known whether RVD occurs during acidification in vitro,
and limited data are available in vivo. Respiratory acidosis (10%
CO2 for 3 h) did not increase cell
water in rat heart, brain, spleen, liver, or skeletal muscle (171),
implying that RVD had occurred. In contrast, exposure of rat skeletal
muscle to 30% CO2 for 95 min
increased cell water by 11% (177), but such severe acidosis may have
overwhelmed or inhibited RVD. In muscle biopsies from humans during
vigorous exercise, there was a small, insignificant increase in
intracellular water despite substantial cellular lactate accumulation
(190), again implying some volume correction.
Because the negative membrane potential is largely responsible for
maintaining cell volume by limiting
Cl accumulation,
depolarization can lead to cell swelling. In vivo, this would be most
apparent in excitable tissues such as nerve and muscle, particularly
where depolarization is due to opening of
Na+ channels. The expected
swelling has in fact been demonstrated in nerve fibers (78) and in
cultured myogenic cells (185). Although the
Na+-K+
pump can rapidly export the excess
Na+, much of this is exchanged for
K+, with the resulting net efflux
of only one osmotically active molecule per cycle. Thus the
Na+-K+
pump is an inefficient volume-regulatory transporter that cannot rapidly relieve cell swelling. Swelling of skeletal muscle during repetitive contraction would be particularly problematic since it could
compromise regional blood flow. Such swelling occurs during vigorous
exercise, accompanied by an increase in
Cl
content (123, 190), but
the swelling cannot be ascribed solely to repetitive depolarization
since acidosis could also contribute to the swelling. The
increase in intracellular water is small, implying that volume
regulation has occurred. Volume regulation via
Ca2+-activated
K+ channels could serve the dual
purpose of repolarizing the membrane potential (15). A dramatic example
of isosmotic swelling in vivo, possibly related to depolarization and
acidosis, occurs after ischemia (39, 215). Although
ischemia directly swells cells in vitro (92), in vivo this may
require reperfusion (215). The marked swelling of endothelium probably
contributes to reduced blood flow and further ischemia, since
perfusion with hypertonic solutions maintains blood vessel patency and
organ perfusion (39), and prevents ischemic damage (2). The cellular
events responsible for cell swelling during reperfusion and the role of
volume-regulatory transporters are unknown.
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CHANGES IN THE SET POINT FOR STEADY-STATE CELL VOLUME |
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Steady-state volume varies over the life span of a cell, particularly
during growth and differentiation. This obviously requires suppression
of normal volume-regulatory mechanisms, but volume-regulatory transporters may also play a more direct role. Activation of NHE1 or
NKCC1 in the absence of cell shrinkage could lead to cell enlargement, whereas volume-independent activation of RVD pathways could lead to
cell shrinkage. Although the role of volume-regulatory transporters in
adjusting steady-state cell volume has not been established, the rapid
activation of NKCC1 (152, 153, 155, 156, and W. C. O'Neill, J. D. Klein, and S. T. Lamitina, unpublished
observations) and NHE1 (60, 175) by growth factors lends
credence to this concept. Addition of serum produces a rapid increase
in cell volume (15% over 10 min) in endothelial cells, which is
mediated by NKCC1 (W. C. O'Neill, J. D. Klein, and S. T. Lamitina, unpublished observations), and a similar response occurs in
growth-stimulated fibroblasts (126, 152, 153). A more chronic
stimulation of NKCC1 is also seen with growth factors (Ref. 19 and W. C. O'Neill, J. D. Klein, and S. T. Lamitina, unpublished observations)
and contributes to the increase in cell volume during the growth cycle
(19). This switch in NKCC1 from its normal mode of
K+/K+
exchange at steady-state volume to a net influx mode implies that
growth stimuli can modulate or overcome the putative inhibitory effect
of intracellular Cl.
Activation of NHE1 by growth factors also increases cell volume (51),
which, like NKCC1, requires disinhibition of the transporter at
steady-state volume, in this case by shifting the pH dependence to the
right (51). The mechanism by which growth factors activate NHE1 and
NKCC1 is not understood. Phosphorylation of NHE1 is increased (178),
but a mutated antiporter lacking phosphorylation sites is still
activated by mitogens, although to a lesser degree (210). Regulation of
NKCC1 by growth factors has not been examined at the molecular level
and, whatever the mechanism, it must overcome the normal inhibition of
net influx (presumably due to intracellular Cl
) to increase cell
volume. Volume-regulatory transporters may also be responsible for cell
enlargement during transformation. Fibroblasts expressing the
ras oncogene were found to be 32%
larger than control cells, with upregulation of both NKCC1 and NHE1
(95, 126), whereas cell enlargement accompanying cytomegalovirus
infection is associated with enhanced activity of NHE1 (27).
Cell shrinkage is an early and dramatic event during apoptosis (6, 7,
149). The mechanism is unknown but appears to be biphasic. In
dexamethasone-treated lymphoid cells, shrinkage begins in 12 h and
progresses until chromatin condensation (36 h). Although this is
associated with a net loss of K+,
other cytoplasmic components are lost as well, since buoyant density
does not change (7). The second phase of shrinkage after chromatin
condensation is due to cellular fragmentation. Apoptotic shrinkage is
inhibited by blocking K+ channels
(6), but it is not known whether these are the normal volume-regulatory
channels. Cell shrinkage also occurs during the latter stages of
erythrocyte maturation and may be mediated by the
K+-Cl
cotransporter (97, 99), which is expressed predominantly in young
erythrocytes (20, 62, 98, 142). Altered regulation of this transporter
may induce additional shrinkage that contributes to sickling in
hemoglobin SS disease (13).
The mechanism that couples cell volume to cell growth and differentiation is unknown. The macromolecular crowding theory of volume regulation could account for the regulation of volume-regulatory transporters by cell growth. As cell content of protein and other macromolecules changes, cell volume would be perceived as too small or too large, and RVI or RVD would be activated. This is consistent with the constant relative content of cell water during the cell cycle in HeLa cells (131) and the constant buoyant density during early apoptosis in lymphoid cells (7), suggesting a constant ratio of macromolecules to cell water. However, this scenario cannot account for the very early activation of NKCC1 and/or NHE1 and the resulting increase in cell volume produced by growth factors well before any increase in protein content. These data are more consistent with coupling in the other direction, with the increase in cell volume stimulating growth. Such coupling of cell growth to cell volume would ensure, for instance, that cells reach a certain size before mitosis. Consistent with this, inhibition of NKCC1 reduces growth responses in endothelial cells (155) and fibroblasts (19, 126, 139, 140, 154, 156) but not in all studies (1). Inhibition of NHE1 also blunts growth responses in a variety of cells (12, 60, 93, 164, 212), but the effect is variable and it is not clear whether it is mediated through changes in cell volume or intracellular pH (8). Because growth factors often activate both NHE1 and NKCC1, dual inhibition may be required to prevent cell swelling, possibly explaining the failure of amiloride or loop diuretics alone to completely inhibit growth. In fact, studies in fibroblasts showed that both were required to completely block DNA synthesis (154). These results suggest that activation of NHE1 and/or NKCC1 leads to an early increase in cell volume that may signal other aspects of cell growth. The role of cell shrinkage in apoptosis is even less clear. Hypertonic shrinkage is reported to both induce (14, 149) and inhibit (55) apoptosis, and prevention of cell shrinkage with K+ channel blockers does not prevent apoptosis (6).
The concept that cell volume controls cell growth is considerably
strengthened by evidence that cell volume also regulates cell
metabolism. Swelling (either hypotonic or isosmotic) of hepatocytes (109, 167, 194) increases protein synthesis and decreases protein degradation, whereas hypertonic shrinkage has the opposite effect (71)
in liver and in other cells (162). Parallel effects are seen on
glycogen synthesis and breakdown (71, 159). This process also
represents a volume-regulatory mechanism, since osmotically active
molecules are consumed during synthesis of protein and glycogen and
released during proteolysis and gycogenolysis. In the liver, changes in
cell volume serve to couple metabolism to nutrient uptake and hormone
action (71). Nutrient uptake and insulin both cause cell swelling (the
latter via stimulation of NKCC1 and NHE1), leading to an increase in
the content of protein and glycogen. Prevention of cell swelling by
inhibiting NKCC1 and NHE1 blocks this anabolic response. On the other
hand, glucagon causes cell shrinkage (probably via opening of
K+ channels), thereby inducing a
catabolic response (proteolysis and glycogenolysis). There is in fact a
linear relationship between hepatocyte volume and protein synthesis and
proteolysis along which many anabolic and catabolic stimuli fall (Fig.
4). The anabolic and catabolic effects of
cell volume may exist in skeletal muscle as well (106-108), but
the role of cell volume in the action of insulin in target tissues
other than liver is unclear (223). The signaling mechanisms by which
cell volume controls cell metabolism and growth are unknown but could
be related to known growth signaling cascades. For instance, cell
swelling has been shown to activate tyrosine kinases, phosphorylate
(and activate) MAP kinases (180, 204), and to increase
c-jun phosphorylation (180),
c-jun mRNA abundance (38), and
phosphorylation of ribosomal protein S6 (109). To what extent any of
these is responsible for the metabolic effects of cell volume is
unknown.
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SUMMARY |
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The purpose of this review is to dispel the notion that cell volume regulation in higher organisms is a curious but physiologically irrelevant phenomenon. Osmolarity of the milieu interieure is not as constant as is often assumed, and significant threats to cell volume still exist in an isosmotic environment under both physiological and pathological conditions. In addition to maintaining cell volume, volume-regulatory mechanisms are also employed to initiate changes in cell volume, as required for cell growth and differentiation. The close link between volume-regulatory transporters, cell volume, and cell growth and metabolism indicates that regulation of cell volume is a fundamental and important property of mammalian cells. The sensing and signaling mechanisms for cell volume regulation remain a mystery, and elucidation of these pathways will provide important new information on other aspects of cell physiology as well.
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ACKNOWLEDGEMENTS |
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I thank Drs. Robert Gunn and Michael Jennings for their helpful comments.
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FOOTNOTES |
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Studies from the author's laboratory have been supported by National Institutes of Health Grants DK-01643, HL-47449, and DK-50268, the National Kidney Foundation of Georgia, and the American Heart Association, Georgia Affiliate.
Address for reprint requests and other correspondence: W. C. O'Neill, Renal Division, Emory Univ. School of Medicine, WMB 338, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail: woneill{at}emory.edu).
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