Renal Physiology

Osmotic Homeostasis
John Danziger and Mark L. Zeidel

Abstract
Alterations in water homeostasis can disturb cell size and function. Although most cells can internally regulate cell
volume in response to osmolar stress, neurons are particularly at risk given a combination of complex cell function
and space restriction within the calvarium. Thus, regulating water balance is fundamental to survival. Through
specialized neuronal osmoreceptors that sense changes in plasma osmolality, vasopressin release and thirst are
Department of
titrated in order to achieve water balance. Fine-tuning of water absorption occurs along the collecting duct, and Medicine, Beth Israel
depends on unique structural modifications of renal tubular epithelium that confer a wide range of water per- Deaconess Medical
meability. In this article, we review the mechanisms that ensure water homeostasis as well as the fundamentals of Center, Boston,
disorders of water balance. Massachusetts
Clin J Am Soc Nephrol 10: 852862, 2015. doi: 10.2215/CJN.10741013
Correspondence:
Dr. John Danziger,
Department of
Crawling out on dry land some millions of years later, regulating extracellular osmolality. The amount of Medicine, Beth Israel
terrestrial forms were faced with the diametrically body water remains remarkably stable despite a huge Deaconess Medical
range of water intake and a multitude of routes for Center, 185 Pilgrim
opposite problems, as least with respect to water. Road, Farr 8, Boston,
Fluid conservation, rather than uid elimination, was water loss, including the respiratory and gastrointes- MA 02215. Email:
the major concern. Instead of discarding their now tinal tract, skin, and the kidneys. In this review, we jdanzige@bidmc.
explore the mechanisms that allow our bodies to harvard.edu
unnecessary pressure lters and redesigning their
respond to a wide range of external inuences, ne-
kidneys as efcient secretory organs, the terrestrial
tuning the exact amount of urinary water excretion to
vertebrates modied and amplied their existing match the bodys immediate needs.
systems to salvage the precious water of the ltrate.
Robert F. Pitts (1)
Maintaining Brain Cell Size
So wrote the great physiologist Robert F. Pitts de- With a plethora of capillaries descending through
scribing the evolution of organisms from the ocean to the subarachnoid space into the parenchyma, the brain is
land (1). Marine animals survive in the high tonicity of remarkably vascular. Astrocytes, star-shaped neuronal
seawater (5001000 mOsm/kg) through a variety of cells, encapsulate the capillaries, forming a blood-brain
mechanisms. The shark maintains a high tonicity in barrier and controlling many important neurologic
its body uids (2,3), whereas dolphins absorb water functions. Although previously thought to be imperme-
from foodstuffs while producing a highly concentrated able (5,6), the discovery of aquaporin (AQP) channels
urine through complex multilobed reniculate kidneys within the astrocyte has elucidated the water perme-
(4). For those of us on land, however, the challenge is ability of this barrier (7) (Figure 1). AQP4 localizes to
not only water conservation but also water elimina- the perivascular and subpial aspects of astrocytes, and
tion, in our world of coffee shops, bottled water, and controls both water efux and inux, as well as regu-
hydration for health philosophies. lates potassium homeostasis, neuronal excitability, in-
Water is the most abundant component of the human ammation, and neuronal signaling (8). By controlling
body, constituting approximately 50%60% of body water movement from brain parenchyma into the sys-
weight. Cell membranes, which dene the intracellular temic circulation, AQP4 regulates brain water content
compartment, and the vascular endothelium, which and volume (9). By controlling water inux, AQP4
denes the intravascular component, are both water plays a role in the signaling cascade that occurs in the
permeable. Because the intracellular space constitutes setting of hypo-osmolarinduced cerebral edema (10).
the largest body compartment, holding approximately Because the amount of intracellular water affects the
two thirds of body uid, changes in water homeostasis concentration of intracellular contents and cell size,
predominantly affect cells; water excess leads to cellu- changes in osmolality can disturb the complex sig-
lar swelling, and water decit leads to cellular shrink- naling network that orchestrates cell function. Given
age. For every 1 liter of water change, approximately the complexity of brain function, even minor changes
666 ml affect the cellular space, with only about 110 ml in neuron ionic composition and size can have pro-
affecting the vascular space. found effects on the processing and transmission of
Although cells have an innate capacity to respond to neuronal signals. Consequently, the brain has devel-
changes in cell volume when extracellular osmolality oped complex osmoregulatory mechanisms to defend
changes, the body protects cells primarily by tightly against changes in plasma osmolality. Within minutes

852 Copyright 2015 by the American Society of Nephrology www.cjasn.org Vol 10 May, 2015
Clin J Am Soc Nephrol 10: 852862, May, 2015 Mechanisms of Water Balance, Danziger and Zeidel 853

Figure 1. | The blood-brain barrier. Penetrating capillaries descend through the subarachnoid space into the parenchyma, and are encased by
astrocytes, which in addition to controlling important neurologic functions, form the blood-brain barrier. AQP4 water channels along the
perivascular and subpial endfoot membranes confer water permeability to the blood-brain barrier. AQP, aquaporin; CSF, cerebrospinal fluid.

of osmolar challenges, brain cells respond by either loss or respond with immediate uptake of surrounding Na1, K1,
accumulation of inorganic osmolytes, returning the cell size and Cl2, correcting cell volume in a process termed regu-
toward normal (11). In the setting of hypotonicity, as latory volume increase (12). With more prolonged exposure,
shown in Figure 2, the rapid swelling of the cell activates organic solute concentrations within the cells rise, replacing
quiescent cell membrane channels and leads to immediate the high levels of ions.
Cl2, K1, and attendant water loss, a process termed regu- Despite these important cell protective mechanisms, alter-
latory volume decrease. Over the subsequent 24 hours, the ations in plasma osmolality can have disastrous consequences.
cells lose further organic solutes, such as myo-inositol, The classic neurologic symptoms of hypo-osmolality, includ-
and amino acids, such as glutamine, glutamate, and tau- ing headache, nausea, vomiting, and if severe enough,
rine. With hyperosmolar-induced cell shrinkage, brain cells seizures, are generally thought to occur at a serum sodium
854 Clinical Journal of the American Society of Nephrology

Figure 2. | Cells regulate their internal volume in response to osmotic stress by activation of membrane carrier proteins and channels. In this
figure, a normal cell is challenged by either a hyperosmolar (left) or hypo-osmolar (right) milieu. In the setting of hyperosmolar stress, whereby
the cell shrinks with water egress, neurons then respond by rapidly accumulating Na1, K1, and Cl2 ions, followed by the production of in-
tracellular organic solutes. The increase of intracellular solute content then draws water in to normalize the concentrations across the cell
membrane, thereby restoring cell size. In the setting of hypo-osmolarinduced swelling, activation of K1 and Cl2 channels, as well as the K1-Cl2
cotransporter, lead to solute and consequent water loss, thereby restoring cell volume.

of 125 mEq/L, although with a wide range of sensitivities that and death. The highest reported serum sodium in the adult
are greatly affected by the rate of osmolality change. More literature remains 255 mEq/L, a consequence of drinking
mild changes of plasma osmolality are also associated with salty water as part of a fatal exorcism ritual (17). Presumably
neurologic symptoms, including gait instability, memory due to the use of table salt as a common antiemetic, fatal salt
impairment, and cognitive decline. Certain groups have an ingestion, either accidentally or voluntarily, is well reported
increased sensitivity to changes in plasma osmolality. Chil- (18), as is accidental iatrogenic administration (19). Seawater
dren are considered at increased risk of hypo-osmolar drowning has also been associated with profound hyperna-
encephalopathy, possibly because of the relatively larger brain tremia (20). In summary, despite internal cellular mecha-
to intracranial volume compared with adults (13). Conversely, nisms to protect cell volume, cells remain at risk with
because the brain begins to atrophy in the sixth decade, el- alterations of water balance; consequently, preventing signif-
derly individuals may be at a lower risk of severe complica- icant changes in plasma osmolality is critical for survival.
tions from acute hyponatremia. In addition to age, sex is also
considered an important determinant of neurologic sensitiv-
ity. The vast majority of reported cases of postoperative hy- Sensing Changes in Body Concentration: The
ponatremia resulting in fatal outcomes have been in women Osmoreceptor
(14), including postpartum and postmenopausal women (15). The ability to internally sense plasma osmolality is
Unlike the brain swelling associated with hypo-osmolality, fundamental to the process of water homeostasis. Much
the brain shrinks in hypertonic conditions. The protective progress in explaining the mechanisms of the osmorecep-
reex of intense thirst may disappear as hypertonicity tor has been made, as reviewed by Sharif-Naeini et al.
worsens, replaced by somnolence, confusion, and muscle (21). Specialized neurons located in several brain areas,
weakness (16). If severe enough, the shrinking brain will pull including the organum vasculosum laminae terminalis
away from the calvarium, tearing the rich capillary plexus, (OVLT) (22,23) and the supraoptic (24,25) and paraventric-
and causing subarachnoid hemorrhage, cerebral bleeding, ular nuclei of the hypothalamus, are able to sense changes
Clin J Am Soc Nephrol 10: 852862, May, 2015 Mechanisms of Water Balance, Danziger and Zeidel 855

in plasma osmolality, responding with complex neuronal hyperosmolality stimulating activity in the anterior wall of
commands. Electrophysiologic recordings from supraoptic the third ventricle, the anterior cingulate, parahippocampal
nuclei of the hypothalamus in rats show an increasing rate gyrus, insula, and the cerebellum (31). These brain regions
of cellular depolarization in response to water deprivation are also associated with complex functions, including emo-
(26), and a decreasing rate with water administration (27). tional behavior and thought, perhaps explaining why the
More recent studies have shown that hyperosmolality perception of thirst, in addition to its physiologic basis, is
causes osmoreceptor membrane depolarization via activation so connected to social and behavioral mores.
of nonselective calcium-permeable cation channels. It re- Hypertonicity is a reproducible stimulus of thirst. The
mains somewhat unresolved whether the exact stimulus osmolar threshold for thirst has traditionally been considered
is change of specic intracellular solutes associated with to be approximately 5 mOsm/kg above the threshold for
cell dehydration or a mechanical effect linked to cell mem- vasopressin release, although some suggest similar set points
brane shrinkage. Identication of the transient receptor (32). A higher thirst threshold allows vasopressin titration of
potential vanilloid (TRPV) family of cation channels as a urinary water excretion without the need to be constantly
potential mechanic-stretch receptor (28) has added sup- drinking. Responding to increasing osmolality, OVLT os-
port to the concept of osmosensing as a mechanical pro- moreceptors relay stimuli to the insula and cingulate cortices
cess (Figure 3), and polymorphisms have been linked to via several medially-located thalamic nuclei, stimulating
hyponatremia (29). Shrinking of OVLT neurons, either by thirst (33). Upon drinking, the sensation of thirst is quenched
dehydration or by negative suction pressure, stimulates cell almost immediately, suggesting that a direct satiating effect
activation via TRPV1 (30). The importance of cell volume in of water on the tongue and buccal membrane as well as
neuronal activation would explain why ineffective osmoles cognitive awareness of uid intake might explain the reso-
that cross the cell membrane, such as urea and glucose (in lution of thirst. In addition, the recent recognition of periph-
the presence of insulin), do not activate the osmoreceptor. eral osmoreceptors located within the gastrointestinal tract
The osmoreceptor, likely because of its role in orchestrating and portal venous system suggest a local mechanism that
the pathways of water retention, has a blunted regulatory directly senses gastric water absorption (34). TRPV-positive
volume decrease response, whereby its own shrinkage due neurons within the thoracic ganglia innervating the liver de-
to hyperosmolality is maintained, allowing sustained stimu- tect changes in local osmolality, and can stimulate a wide
lation of thirst and vasopressin release until the plasma os- array of physiologic responses, including modulation of BP
molality can be corrected (30). In the following sections, we (35), metabolism (36), and water homeostasis. Whether these
discuss how the osmoreceptor regulates thirst and vasopres- peripheral osmoreceptors might contribute to the disorders
sin (synonymously known as antidiuretic hormone) release. of osmolality frequently seen in patients with cirrhosis re-
mains unknown.
In addition to osmotic stimuli, there are important non-
Thirst osmotic stimuli of thirst. The hemodynamics of hemorrhage
The sensation of thirst is the experiential component of are potently dipsogenic. Thirst on the battleeld is legendary,
the complex physiologic drive to drink. Neuroimaging with exsanguinating soldiers asking for water. In animal
studies have localized the anatomic origin of thirst, with models, hemorrhage stimulates intense water drinking (37),

Figure 3. | Osmoreceptor functions of the OVLT nuclei and SON control thirst and vasopressin release, respectively. In response to
hyperosmolar-induced cell shrinkage, specialized mechanical-stretch TRPV cation channels are activated, allowing the influx of positive charges
and consequent cell depolarization, provoking action potentials that stimulate thirst and vasopressin release. Conversely, hypo-osmolar cell
swelling deactivates these channels, leading to cell hyperpolarization, extinguishing thirst and vasopressin release. Although the exact role of
the TRPV channel remains under investigation, its presence is critical in this mechanism. OVLT, organum vasculosum laminae terminalis; SON,
supraoptic nuclei; TRPV, transient receptor potential vanilloid.
856 Clinical Journal of the American Society of Nephrology

which is more easily extinguished by drinking saltwater osmolality. Early physiologic experiments on dogs using ei-
than plain water (38,39). Angiotensin II, when injected into ther hemorrhage or transfusion illustrated that circulatory
sensitive areas of the brain (40,41) or when injected system- blood volume modied the association between plasma os-
ically, is a powerful stimulus for water intake, as is activa- molality and vasopressin (54). For any given plasma osmo-
tion of the renin-angiotensin axis (42), providing a lality, hemorrhage was associated with a higher vasopressin
mechanistic explanation for the association of thirst with ab- concentration, whereas transfusion was associated with a
normalities of body uid volume. Thirst is a common com- lower vasopressin concentration. In these experiments, hem-
plaint for patients with congestive heart failure (43,44), orrhage and transfusion were associated with a change in
frequently plagues dialysis patients, and likely contributes left atrial pressure, but not BP.
to the prevalence of hyponatremia in these populations. Although myriad terms, such as intravascular volume,
Pharmacologic blockade of the renin-angiotensin axis, al- effective arterial volume, or circulatory volume, have been
though theoretically attractive, does not seem to reduce used to describe the component of body uid that effec-
thirst (45). In addition to disorders of uid volume, thirst tively perfuses critical organs, these terms imply that the
is also frequently encountered in patients with psychiatric vascular compartment is readily measurable, a feat that is
disorders, reported in up to 25% of hospitalized patients difcult in the laboratory and impossible at the bedside.
with schizophrenia. Although this might be in part due to Furthermore, because the vascular endothelium is freely
compulsive behavior or the anticholinergic side effects of permeable to water and sodium, the intravascular and in-
psychotropic medications, studies have suggested an alter- terstitial compartments freely and dynamically communi-
ation of the sensation of thirst in patients with mental illness, cate, further limiting the idea of a separate, quantiable
with a lower osmolar threshold (46). intravascular space. Instead, because pressure receptors
located in the heart and carotid arteries and ow receptors
in the juxtaglomerular apparatus are the sensors for body
Vasopressin uid volume, we favor the simple term sensed volume (55).
Vasopressin is a potent endogenous peptide inuencing a Arterial baroreceptors, through cranial nerves IX and X,
wide array of biologic functions, including regulation of communicate with the hypothalamus and can modify va-
water balance, BP, platelet function, and thermoregulation sopressin release. Sensed volume depletion, in the setting
(4749). It is synthesized as a prohormone in the magno- of true volume depletion (e.g., diarrhea or vomiting) or
cellular cell bodies of the paraventricular and supraoptic volume overload (e.g., heart failure and cirrhosis), both
nuclei of the posterior hypothalamus, and by binding to amplify the sensitivity to vasopressin so that for any given
the carrier protein neurohypophysin, it is transported plasma osmolality, the urinary osmolality is greater.
along the supraoptic hypophyseal tract to the axonal ter- In summary, the osmoreceptor is stimulated by both
minals of magnocellular neurons in the posterior pituitary. osmotic and nonosmotic stimuli to initiate thirst and to
Synthesis and storage take approximately 2 hours, with a release vasopressin in order to maintain water balance.
t1/2 of 2030 minutes, metabolized by vasopressinases in
the liver and kidney. Vasopressin acts on V1, V2, V3, and
oxytocin-type receptors. V1 receptors are located on the A Highly Concentrated Medulla
vasculature, myometrium, and platelets. V3 receptors are We previously described how the body senses and re-
mainly found in the pituitary. V2 receptors are located sponds to changes in plasma osmolality. Next we turn to the
along the distal tubule and collecting duct. nal steps of osmotic homeostasis: renal water retention or
The most sensitive stimulus for vasopressin release is excretion. Having a highly concentrated medullary intersti-
increasing plasma osmolality. Whereas normal vasopressin tium is essential for water conservation, providing the osmotic
concentrations are 0.55 pg/ml in fasted, hydrated indi- force for water egress from ltered renal tubular uid. The
viduals (50), subtle increases in plasma osmolality, often in medulla, reaching up to four times the concentration of the
the range of ,2% of body water, stimulate the osmorecep- surrounding interstitial uid, is like a concentration oasis or a
tor to release vasopressin, and serum concentrations rap- pocket of hypertonic uid within a deeply vascular organ
idly increase 3-fold. The presence of stored vasopressin in unprotected by a barrier epithelium. The generation and
the pituitary guarantees a rapid and effective mechanism maintenance of the medullary interstitial gradient is one of the
of water regulation. As water is retained and the plasma fundamental teachings of renal physiology (Figure 4).
osmolality returns to normal, the stimuli for vasopressin Generating the medullary concentration depends on three
release is extinguished. important structural modications of the renal tubule. First, a
In addition, there are nonosmotic stimuli, including NE, hairpin loop in the renal tubule allows solute and water
dopamine, pain, hypoxia, and acidosis (51), and most im- exchange between the descending thin limb and the ascend-
portantly, circulatory hemodynamics. Cardiovascular col- ing thick limb. Second, the combination of the highly energy-
lapse is associated with profound vasopressin release, with dependent Na/K-ATPase and the NaK2Cl cotransporter,
concentrations 100-fold greater than normal (52), presum- along with the apical water impermeability of the thick as-
ably because greater vasopressin concentrations are needed cending limb, drive solute without water egress from the
to increase systolic BP than to regulate antidiuresis. Such medulla. Third, because the descending limb is water per-
high concentrations rapidly exhaust the pituitary vasopres- meable, the exiting sodium from the thick ascending limb
sin stores, and given the time-consuming nature of vasopres- creates a concentration gradient that pulls water from the
sin production, vasopressin depletion is thought contributory descending limb, and as that tubular uid then moves into the
to shock physiology (53). Subtle changes in body uid vol- ascending limb, the NaK2Cl cotransporter is presented with
ume modify the responsiveness of vasopressin release to increasingly concentrated tubular uid, further generating
Clin J Am Soc Nephrol 10: 852862, May, 2015 Mechanisms of Water Balance, Danziger and Zeidel 857

Figure 4. | The medullary interstitium has a concentration >4 times that of its surrounding fluid, and must be both generated and maintained.
The countercurrent multiplier, composed of a hairpin tubule loop with a water-permeable descending limb juxtaposed against an impermeable
ascending limb with a highly active Na-K-2Cl pump, generates the concentration gradient. A separate hairpin loop within the tubular capillary
system allows shunting of water from the descending limb to the ascending limb preventing the dilution of the medullary gradient. This process,
countercurrent exchange, maintains the medullary concentration.

more of an interstitial concentration. This process, termed medullary glomeruli (57,58). Second, for the vasa rectae
countercurrent multiplication, is responsible for generation of that descend into the medulla, a hairpin loop prevents
approximately one half (600 mOsm/kg) of the maximal med- medullary dilution, a process known as countercurrent ex-
ullary concentration gradient (1200 mOsm/kg), with the re- change. In a manner similar to the vascular structure of a
mainder being generated by urea recycling (56). penguins webbed foot that allows heat conservation despite
Given that the kidneys receive approximately 25% of walking on ice, whereby the warmth of descending blood
cardiac output, with the potential to rapidly wash away shuttles to the ascending limb and bypasses the colder distal
any area of hyperosmolarity, maintaining the medullary loop, the vasa rectas hairpin loop prevents water from
concentration is fundamental. There are two major mech- reaching the distal aspects of the circuit, preventing medul-
anisms to prevent medullary washout. First, the majority lary washout (59). In essence, these mechanisms shunt water
of renal blood ow is directed to supercial glomeruli away from the highly concentrated deep medulla, protecting
limited to the outer cortex, with ,2% perfusing the deep it as a pocket of highly concentrated uid. This combination
858 Clinical Journal of the American Society of Nephrology

Figure 5. | Vasopressin regulates AQP2 expression. In the presence of vasopressin, increased production of cAMP activates PKA, which in turn
phosphorylates stored AQP-containing vesicles, and targets them to the apical membrane, increasing its water permeability, and facilitating
water reclamation from the lumen. In the absence of vasopressin, AQP2 is endocytosed and internally degraded, conferring water imper-
meability to the apical membrane, thereby maximizing water excretion. AQP3 and AQP4, constitutively expressed on the basolateral
membrane, allow water egress from the cell. PKA, protein kinase A; V2R, vasopressin 2 receptor.

of building and maintaining a concentrated medulla pro- more concentrated interstitium. The water permeabilities of
vides the force for tubular water egress and allows the the different sections of the tubule are determined by the
ne-tuning of water balance, discussed next. presence or absence of important structural modications that
control both the paracellular and transcellular routes of ow.
Fine-Tuning Water Balance in the Collecting Duct Tight junction proteins, including cytoplasmic scaffolding
The ability of the nephron to excrete a urine that is more proteins, transmembrane proteins, and signaling proteins, act
concentrated than the plasma (water reabsorption) or more like a biologic zipper, controlling movement of water and
dilute than the plasma (water excretion) relies on the solutes in the intercellular passageway (60). Zona occludens
presence of nephron segments that are extremely permeable protein-1 functions as a scaffold protein, anchoring to other
to water, as well as segments that are nearly impermeable. To transmembrane proteins and the actin cytoskeleton, help-
excrete dilute urine, the collecting duct must be able to ing to seal the intercellular space. The expression of zona
maintain an almost 30-fold concentration gradient between occludens protein-1 may respond directly to changes in med-
the dilute urinary ltrate and the surrounding highly con- ullary tonicity (61), suggesting a local level of permeability reg-
centrated medullary interstitium. Conversely, in order to con- ulation. Claudins are key integral membrane proteins that
serve water, the collecting duct must alter its water function as high-conductance cation pores, regulating the
permeability, allowing the egress of ltrate water into the transcellular movement of sodium, magnesium, and calcium
Clin J Am Soc Nephrol 10: 852862, May, 2015 Mechanisms of Water Balance, Danziger and Zeidel 859

(62). In addition to their role in the impermeability of the renal the basolateral membranes of the proximal tubule and de-
tubule, the tight junctions control gastrointestinal permeabil- scending limb, providing a route for transcellular move-
ity (63) and have been associated with a wide range of di- ment, but is absent in the thick ascending limb. AQP2,
arrheal illness, including Crohns disease (64,65). The which is expressed along the apical membrane of collecting
expression of tight junction proteins increases along the duct principal cells, is regulated by vasopressin. Upon bind-
length of the tubule, particularly along the thick ascending ing to its receptor in the basolateral membrane, vasopressin
limb and the collecting duct (66,67). initiates a complex cascade of signals that ultimately result in
In addition to controlling the paracellular route, the the movement of AQP2 channels to the apical membrane,
collecting duct must prevent the transcellular movement of rendering the cell water permeable. The biologic details of
water. Recent work has provided a mechanistic explanation this complex mechanism have largely been elucidated. As
for how barrier epithelial cells achieve this transcellular seen in Figure 5, binding of vasopressin to the vasopressin
impermeability (6870). Although once thought to be simply V2 receptor on the basolateral membrane activates adenylate
due to the depth of the cell barrier, important modications cyclase, increasing intracellular cAMP levels, activating pro-
within the apical cell membrane are likely responsible for tein kinase A, and leading to the translocation of AQP2 bear-
barrier impermeability (71,72). Barrier epithelia segregate ing vesicles to the apical membrane. Upon withdrawal of
high levels of glycosphingolipid, which entraps cholesterol, vasopressin, AQP2 is internalized into intracellular storage
as well as long, relatively saturated fatty acidladen triglyc- vesicles. In addition to the short-term regulation of AQP2 traf-
erides, in their outer leaets. This composition leads to tight cking, vasopressin also inuences the long-term expression
packing of the triglycerides, so that nearly all of the surface is of AQP2 in collecting ducts, increasing their abundance. AQP2
composed of phosphate headgroups, which impede water expression is also thought to be controlled by vasopressin-
ow. Water that does nd the surface and penetrates has independent mechanisms, including other transcription
difculty diffusing across the space between the chains be- factors (76), oxytocin (77), and possibly the novel hormone
cause of tight packing caused by cholesterol (73,74). secretin (78).
Finally, water movement across the renal tubule also As seen in Figure 6, the distribution of tight junctions and
depends on the presence of AQP channels, as reviewed by AQP channels, along with unique barrier qualities of renal
Agre (75). AQP1 is constitutively present in the apical and tubular epithelium, determine the water permeability of the

Figure 6. | Water permeability along the tubule is determined by the presence or absence of intracellular tight junctions and AQP water
channels. AQP1, along the proximal tubule and thin descending limb, is constitutively expressed, whereas AQP2, in the collecting duct, is
under the control of vasopressin. The presence of AQP1 and the absence of tight junctions render the proximal tubule permeable, facilitating
filtered solute and water reclamation (91). In the thin descending limb, the presence of AQP1 and tight junctions (claudin 2) render it water
permeable but solute impermeable (92). Conversely, the impermeability of the thick ascending limb results from extensive tight junctions and
absent AQP channels. The collecting duct is unique in its homeostatic responsiveness. In times of water conservation, vasopressin (AVP) binds
to vasopressin 2 receptors (V2R), inducing AQP2 channel expression and consequent water retention, and in times of water excess, AQP2
retreats from the apical membrane due to vasopressins absence.
860 Clinical Journal of the American Society of Nephrology

renal tubule. The collecting duct is unique in its capacity to volume depletion (e.g., diarrhea or vomiting) or volume
rapidly alter its water permeability under the tutelage of overload (e.g., cirrhosis or congestive heart failure). Con-
vasopressin, allowing ne-tuning of water excretion and versely, the syndrome of inappropriate antidiuretic hor-
guarding water homeostasis. mone (SIADH) secretion manifests as an inability to
excrete water due to insuppressible vasopressin activity.
The diagnosis of SIADH requires the absence of sensed
Clinical Correlation volume depletion, and an inappropriately concentrated
Diabetes insipidus, a failure of water conservation re- urine in the setting of hypo-osmolality, and occurs in a
sulting in hyperosmolarity and compensatory polydipsia, wide range of settings, including neurologic and pulmo-
is frequently encountered in clinical practice. Central diabetes nary disease, medications, pain, and nausea (86). Recent
insipidus can result from traumatic, surgical, or ischemic gain-of-functions mutations in the vasopressin gene have
injury at any site of vasopressin production, but is most often been described, causing a SIADH-like clinical picture
idiopathic, possibly due to autoimmune destruction of with undetectable vasopressin levels, termed nephrogenic
vasopressin (79). Hereditary forms, termed familial neurohy- syndrome of inappropriate antidiuresis (87).
pophyseal diabetes insipidus, are caused by mutations in the Multiple studies have linked hyponatremia to increased
vasopressin gene, resulting in protein misfolding and de- mortality, with an increased risk ranging from 2-fold (88) to
generation of the vasopressin-producing magnocellular as much as 60-fold (89). Given the wide range of underly-
neurons. Genetic abnormalities are also associated with ing pathologies potentially associated with hyponatremia,
nephrogenic diabetes insipidus (80), with mutations in the and the difculty in adequately controlling for residual
vasopressin 2 receptor gene as the most common cause. Pro- confounding, these observational studies should be inter-
tein misfoldings trap the vasopressin 2 receptor gene within preted with some caution. Although most studies have
the cells endoplasmic reticulum, preventing it from docking shown a linear inverse effect of decreasing sodium with
with circulating vasopressin (81). These mutations are inheri- mortality, recent studies have suggested a parabolic phe-
ted in an X-linked pattern; hence, male individuals tended to nomenon, whereby the increased mortality associated
have more pronounced concentration defects, whereas fe- with serum sodium in the mid-120 mEq/l range dissipates
male individuals are usually asymptomatic. Mutations in at concentrations ,120 mEq/l (90). Given the risks asso-
the AQP2 gene, which can be inherited in a recessive or ciated with correcting hyponatremia, including central
dominant fashion, are associated with defects in trafcking pontine myelinosis and volume overload, prospective
of the water channel to the apical membrane. In addition to studies are needed to further clarify the relationship of
these genetic causes, lithium use frequently causes diabetes hyponatremia to outcomes.
insipidus, occurring in approximately 40% of chronic lithium In summary, water homeostasis depends on a functional
users (82). It is associated with downregulation of AQP2 and and sensitive osmoreceptor, intact vasopressin and thirst
cellular remodeling of the collecting duct. The route of lith- mechanisms, and a renal tubule that can respond to the
ium toxicity is thought to be due to cellular uptake via the tightly orchestrated commands that dictate water retention
epithelial Na channel (83), and although experimental data or excretion.
suggest that amiloride administration may prevent lithium
Acknowledgments
nephrotoxicity (84), clinical data are lacking.
J.D. is supported by a Normon S. Coplon Extramural Grant from
Hyponatremia is the most common electrolyte distur-
Satellite Healthcare.
bance (85) and results from water intake, either orally or
intravenously, in excess of excretion. For normal
Disclosures
individuals, a water load will extinguish the osmoreceptor None.
stimulation of thirst and vasopressin release, allowing for
dilution of the urine down to ,50 mOsm/kg, and rapid
water excretion. Given that the average solute load of av- References
erage diets is approximately 800 mOsm, primarily in the 1. Pitts RF: Physiology of the Kidney and Body Fluids, Chicago, Year
form of protein and sodium, most individuals can excrete Book Medical Publishers, 1963
2. Epstein FH: The shark rectal gland: A model for the active
up to 16 liters of water, and thus can drink similar amounts transport of chloride. Yale J Biol Med 52: 517523, 1979
before becoming hyponatremic. The classic disorders of tea 3. Silva P, Stoff J, Field M, Fine L, Forrest JN, Epstein FH: Mechanism
and toast or beer potomania occur in the setting of low- of active chloride secretion by shark rectal gland: Role of Na-K-
solute diets (i.e., carbohydrates that are rapidly converted to ATPase in chloride transport. Am J Physiol 233: F298F306, 1977
4. Ortiz RM: Osmoregulation in marine mammals. J Exp Biol 204:
water without providing solute) combined with high water 18311844, 2001
intake, thus allowing hyponatremia to develop at much 5. Crone C, Olesen SP: Electrical resistance of brain microvascular
more modest amounts of water intake. For true psychogenic endothelium. Brain Res 241: 4955, 1982
polydipsia, as dened by an ability to overwhelm the kid- 6. Crone C, Christensen O: Electrical resistance of a capillary en-
neys capacity to excrete water through dilute urine, patients dothelium. J Gen Physiol 77: 349371, 1981
7. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre
must drink huge amounts of uid. Hyponatremia with a P, Ottersen OP: Specialized membrane domains for water
urine osmolality.100 mOsm/kg signies the presence and transport in glial cells: High-resolution immunogold cytochem-
action of vasopressin. Because serum osmolality is the nor- istry of aquaporin-4 in rat brain. J Neurosci 17: 171180, 1997
mal driver for vasopressin release, its presence at low serum 8. Nagelhus EA, Ottersen OP: Physiological roles of aquaporin-4 in
brain. Physiol Rev 93: 15431562, 2013
osmolality suggests concentration-independent mechanisms 9. Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA,
of vasopressin release. As noted above, sensed volume de- Skare , Laake P, Klungland A, Thoren AE, Burkhardt JM,
pletion can stimulate vasopressin release. This can occur in Ottersen OP, Nagelhus EA: Glial-conditional deletion of
Clin J Am Soc Nephrol 10: 852862, May, 2015 Mechanisms of Water Balance, Danziger and Zeidel 861

aquaporin-4 (Aqp4) reduces blood-brain water uptake and con- 32. Thompson CJ, Bland J, Burd J, Baylis PH: The osmotic thresholds
fers barrier function on perivascular astrocyte endfeet. Proc Natl for thirst and vasopressin release are similar in healthy man. Clin
Acad Sci U S A 108: 1781517820, 2011 Sci (Lond) 71: 651656, 1986
10. Thrane AS, Rappold PM, Fujita T, Torres A, Bekar LK, Takano T, 33. Hollis JH, McKinley MJ, DSouza M, Kampe J, Oldfield BJ: The
Peng W, Wang F, Rangroo Thrane V, Enger R, Haj-Yasein NN, trajectory of sensory pathways from the lamina terminalis to the
Skare , Holen T, Klungland A, Ottersen OP, Nedergaard M, insular and cingulate cortex: A neuroanatomical framework for
Nagelhus EA: Critical role of aquaporin-4 (AQP4) in astrocytic the generation of thirst. Am J Physiol Regul Integr Comp Physiol
Ca21 signaling events elicited by cerebral edema. Proc Natl 294: R1390R1401, 2008
Acad Sci U S A 108: 846851, 2011 34. Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm
11. Chamberlin ME, Strange K: Anisosmotic cell volume regulation: S, May M, Pischke S, Suzuki M, Iba~ nez-Tallon I, Luft FC, Jordan J,
A comparative view. Am J Physiol 257: C159C173, 1989 Lewin GR: The molecular and cellular identity of peripheral
12. Cserr HF, DePasquale M, Nicholson C, Patlak CS, Pettigrew KD, osmoreceptors. Neuron 69: 332344, 2011
Rice ME: Extracellular volume decreases while cell volume is 35. McHugh J, Keller NR, Appalsamy M, Thomas SA, Raj SR,
maintained by ion uptake in rat brain during acute hyper- Diedrich A, Biaggioni I, Jordan J, Robertson D: Portal osmo-
natremia. J Physiol 442: 277295, 1991 pressor mechanism linked to transient receptor potential
13. Arieff AI, Ayus JC, Fraser CL: Hyponatraemia and death or per- vanilloid 4 and blood pressure control. Hypertension 55: 1438
manent brain damage in healthy children. BMJ 304: 12181222, 1443, 2010
1992 36. Boschmann M, Steiniger J, Franke G, Birkenfeld AL, Luft FC,
14. Ayus JC, Arieff AI: Chronic hyponatremic encephalopathy in Jordan J: Water drinking induces thermogenesis through osmo-
postmenopausal women: Association of therapies with morbidity sensitive mechanisms. J Clin Endocrinol Metab 92: 33343337,
and mortality. JAMA 281: 22992304, 1999 2007
15. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic en- 37. Russell PJ, Abdelaal AE, Mogenson GJ: Graded levels of hemor-
cephalopathy in menstruant women. Ann Intern Med 117: 891 rhage, thirst and angiotensin II in the rat. Physiol Behav 15: 117
897, 1992 119, 1975
16. Snyder NA, Feigal DW, Arieff AI: Hypernatremia in elderly pa- 38. Stricker EM: Inhibition of thirst in rats following hypovolemia
tients. A heterogeneous, morbid, and iatrogenic entity. Ann In- and-or caval ligation. Physiol Behav 6: 293298, 1971
tern Med 107: 309319, 1987 39. Stricker EM: Osmoregulation and volume regulation in rats: In-
17. Ofran Y, Lavi D, Opher D, Weiss TA, Elinav E: Fatal voluntary salt hibition of hypovolemic thirst by water. Am J Physiol 217: 98
intake resulting in the highest ever documented sodium plasma 105, 1969
level in adults (255 mmol L-1): A disorder linked to female gender 40. el Ghissassi M, Thornton SN, Nicoladis S: Angiotensin II-
and psychiatric disorders. J Intern Med 256: 525528, 2004 induced thirst, but not sodium appetite, via AT1 receptors in
18. Addleman M, Pollard A, Grossman RF: Survival after severe hy- organum cavum prelamina terminalis. Am J Physiol 268: R1401
pernatremia due to salt ingestion by an adult. Am J Med 78: 176 R1405, 1995
178, 1985 41. Weisinger RS, Blair-West JR, Burns P, Denton DA, Tarjan E: Role
19. Calvin ME, Knepper R, Robertson WO: Hazards to health. Salt of brain angiotensin in thirst and sodium appetite of rats. Peptides
poisoning. N Engl J Med 270: 625626, 1964 18: 977984, 1997
20. Ellis RJ: Severe hypernatremia from sea water ingestion during 42. Leenen FH, Stricker EM: Plasma renin activity and thirst follow-
near-drowning in a hurricane. West J Med 167: 430433, 1997 ing hypovolemia or caval ligation in rats. Am J Physiol 226: 1238
21. Sharif-Naeini R, Ciura S, Zhang Z, Bourque CW: Contribution of 1242, 1974
TRPV channels to osmosensory transduction, thirst, and vaso- 43. Waldreus N, Sjostrand F, Hahn RG: Thirst in the elderly with and
pressin release. Kidney Int 73: 811815, 2008 without heart failure. Arch Gerontol Geriatr 53: 174178, 2011
22. Vivas L, Chiaraviglio E, Carrer HF: Rat organum vasculosum 44. Waldreus N, Hahn RG, Jaarsma T: Thirst in heart failure: A sys-
laminae terminalis in vitro: Responses to changes in sodium tematic literature review. Eur J Heart Fail 15: 141149, 2013
concentration. Brain Res 519: 294300, 1990 45. Masajtis-Zagajewska A, Nowicki M: Influence of dual blockade
23. Ciura S, Bourque CW: Transient receptor potential vanilloid 1 is of the renin-angiotensin system on thirst in hemodialysis patients.
required for intrinsic osmoreception in organum vasculosum Nephron Clin Pract 112: c242c247, 2009
lamina terminalis neurons and for normal thirst responses to 46. Goldman MB, Luchins DJ, Robertson GL: Mechanisms of altered
systemic hyperosmolality. J Neurosci 26: 90699075, 2006 water metabolism in psychotic patients with polydipsia and hy-
24. Leng G, Mason WT, Dyer RG: The supraoptic nucleus as an os- ponatremia. N Engl J Med 318: 397403, 1988
moreceptor. Neuroendocrinology 34: 7582, 1982 47. Ishikawa SE, Schrier RW: Pathophysiological roles of arginine
25. Mason WT: Supraoptic neurones of rat hypothalamus are os- vasopressin and aquaporin-2 in impaired water excretion. Clin
mosensitive. Nature 287: 154157, 1980 Endocrinol (Oxf) 58: 117, 2003
26. Walters JK, Hatton GI: Supraoptic neuronal activity in rats during 48. Martin PY, Abraham WT, Lieming X, Olson BR, Oren RM, Ohara
five days of water deprivation. Physiol Behav 13: 661667, 1974 M, Schrier RW: Selective V2-receptor vasopressin antagonism
27. Brimble MJ, Dyball RE: Characterization of the responses of decreases urinary aquaporin-2 excretion in patients with chronic
oxytocin- and vasopressin-secreting neurones in the supraoptic heart failure. J Am Soc Nephrol 10: 21652170, 1999
nucleus to osmotic stimulation. J Physiol 271: 253271, 1977 49. Schrier RW: Vasopressin and aquaporin 2 in clinical disorders of
28. Liedtke W, Choe Y, Mart-Renom MA, Bell AM, Denis CS, Sali A, water homeostasis. Semin Nephrol 28: 289296, 2008
Hudspeth AJ, Friedman JM, Heller S: Vanilloid receptor-related 50. Cowley AW Jr, Cushman WC, Quillen EW Jr, Skelton MM,
osmotically activated channel (VR-OAC), a candidate vertebrate Langford HG: Vasopressin elevation in essential hypertension
osmoreceptor. Cell 103: 525535, 2000 and increased responsiveness to sodium intake. Hypertension 3:
29. Tian W, Fu Y, Garcia-Elias A, Fernandez-Fernandez JM, Vicente I93I100, 1981
R, Kramer PL, Klein RF, Hitzemann R, Orwoll ES, Wilmot B, 51. Leng G, Brown CH, Russell JA: Physiological pathways regulat-
McWeeney S, Valverde MA, Cohen DM: A loss-of-function ing the activity of magnocellular neurosecretory cells. Prog
nonsynonymous polymorphism in the osmoregulatory TRPV4 Neurobiol 57: 625655, 1999
gene is associated with human hyponatremia. Proc Natl Acad Sci 52. Cowley AW Jr, Switzer SJ, Guinn MM: Evidence and quantifi-
U S A 106: 1403414039, 2009 cation of the vasopressin arterial pressure control system in the
30. Ciura S, Liedtke W, Bourque CW: Hypertonicity sensing in organum dog. Circ Res 46: 5867, 1980
vasculosum lamina terminalis neurons: A mechanical process in- 53. Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M,
volving TRPV1 but not TRPV4. J Neurosci 31: 1466914676, 2011 Raphael JC, Gajdos P, Annane D: Depletion of neurohypophyseal
31. Egan G, Silk T, Zamarripa F, Williams J, Federico P, Cunnington R, content of vasopressin in septic shock. Crit Care Med 30: 497
Carabott L, Blair-West J, Shade R, McKinley M, Farrell M, 500, 2002
Lancaster J, Jackson G, Fox P, Denton D: Neural correlates of the 54. Quillen EW Jr, Cowley AW Jr: Influence of volume changes on
emergence of consciousness of thirst. Proc Natl Acad Sci U S A osmolality-vasopressin relationships in conscious dogs. Am J
100: 1524115246, 2003 Physiol 244: H73H79, 1983
862 Clinical Journal of the American Society of Nephrology

55. Danziger J, Zeidel M, Parker MJ: Renal Physiology: A Clinical 76. Hasler U, Jeon US, Kim JA, Mordasini D, Kwon HM, Feraille E,
Approach, Baltimore, Lippincott Williams and Wilkins, 2012 Martin PY: Tonicity-responsive enhancer binding protein is an
56. Epstein FH, Kleeman CR, Pursel S, Hendrikx A: The effect of essential regulator of aquaporin-2 expression in renal collecting
feeding protein and urea on the renal concentrating process. duct principal cells. J Am Soc Nephrol 17: 15211531, 2006
J Clin Invest 36: 635641, 1957 77. Jeon US, Joo KW, Na KY, Kim YS, Lee JS, Kim J, Kim GH, Nielsen
57. Moffat DB, Fourman J: The vascular pattern of the rat kidney. S, Knepper MA, Han JS: Oxytocin induces apical and basolateral
J Anat 97: 543553, 1963 redistribution of aquaporin-2 in rat kidney. Nephron, Exp
58. Moffat DB, Fourman J: A vascular pattern of the rat kidney. 1963. Nephrol 93: e36e45, 2003
J Am Soc Nephrol 12: 624632, 2001 78. Chu JY, Chung SC, Lam AK, Tam S, Chung SK, Chow BK: Phe-
59. Pallone TL, Edwards A, Mattson DL: Renal medullary circulation. notypes developed in secretin receptor-null mice indicated a role
Compr Physiol 2: 97140, 2012 for secretin in regulating renal water reabsorption. Mol Cell Biol
60. Denker BM, Sabath E: The biology of epithelial cell tight junc- 27: 24992511, 2007
tions in the kidney. J Am Soc Nephrol 22: 622625, 2011 79. Pivonello R, De Bellis A, Faggiano A, Di Salle F, Petretta M, Di
61. Then C, Bergler T, Jeblick R, Jung B, Banas B, Kramer BK: Hy- Somma C, Perrino S, Altucci P, Bizzarro A, Bellastella A,
pertonic stress promotes the upregulation and phosphorylation of Lombardi G, Colao A: Central diabetes insipidus and autoim-
zonula occludens 1. Nephron, Physiol 119: 1121, 2011 munity: Relationship between the occurrence of antibodies to
62. Hou J, Rajagopal M, Yu AS: Claudins and the kidney. Annu Rev arginine vasopressin-secreting cells and clinical, immunologi-
Physiol 75: 479501, 2013 cal, and radiological features in a large cohort of patients with
63. Shen L, Turner JR: Role of epithelial cells in initiation and prop- central diabetes insipidus of known and unknown etiology. J Clin
agation of intestinal inflammation. Eliminating the static: Tight Endocrinol Metab 88: 16291636, 2003
junction dynamics exposed. Am J Physiol Gastrointest Liver 80. Fujiwara TM, Bichet DG: Molecular biology of hereditary di-
Physiol 290: G577G582, 2006 abetes insipidus. J Am Soc Nephrol 16: 28362846, 2005
64. Howden CW, Gillanders I, Morris AJ, Duncan A, Danesh B, 81. Morello JP, Salahpour A, Laperrie`re A, Bernier V, Arthus MF,
Russell RI: Intestinal permeability in patients with Crohns dis- Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG,
ease and their first-degree relatives. Am J Gastroenterol 89: Bouvier M: Pharmacological chaperones rescue cell-surface
11751176, 1994 expression and function of misfolded V2 vasopressin receptor
65. Katz KD, Hollander D, Vadheim CM, McElree C, Delahunty T, mutants. J Clin Invest 105: 887895, 2000
Dadufalza VD, Krugliak P, Rotter JI: Intestinal permeability in 82. Stone KA: Lithium-induced nephrogenic diabetes insipidus. J Am
patients with Crohns disease and their healthy relatives. Gas- Board Fam Pract 12: 4347, 1999
troenterology 97: 927931, 1989 83. Christensen BM, Zuber AM, Loffing J, Stehle JC, Deen PM,
66. Gonzalez-Mariscal L, Namorado MC, Martin D, Luna J, Alarcon Rossier BC, Hummler E: alphaENaC-mediated lithium absorp-
L, Islas S, Valencia L, Muriel P, Ponce L, Reyes JL: Tight junction tion promotes nephrogenic diabetes insipidus. J Am Soc Nephrol
proteins ZO-1, ZO-2, and occludin along isolated renal tubules. 22: 253261, 2011
Kidney Int 57: 23862402, 2000 84. Kortenoeven ML, Li Y, Shaw S, Gaeggeler HP, Rossier BC,
67. Gonzalez-Mariscal L, Namorado Mdel C, Martin D, Sierra G, Wetzels JF, Deen PM: Amiloride blocks lithium entry through the
Reyes JL: The tight junction proteins claudin-7 and -8 display a sodium channel thereby attenuating the resultant nephrogenic
different subcellular localization at Henles loops and collecting diabetes insipidus. Kidney Int 76: 4453, 2009
ducts of rabbit kidney. Nephrol Dial Transplant 21: 23912398, 85. Upadhyay A, Jaber BL, Madias NE: Incidence and prevalence of
2006 hyponatremia. Am J Med 119[Suppl 1]: S30S35, 2006
68. Nagle JF, Mathai JC, Zeidel ML, Tristram-Nagle S: Theory of 86. Robertson GL: Regulation of arginine vasopressin in the syn-
passive permeability through lipid bilayers. J Gen Physiol 131: drome of inappropriate antidiuresis. Am J Med 119[Suppl 1]:
7785, 2008 S36S42, 2006
69. Mathai JC, Tristram-Nagle S, Nagle JF, Zeidel ML: Structural de- 87. Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA,
terminants of water permeability through the lipid membrane. Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller
J Gen Physiol 131: 6976, 2008 WL, Gitelman SE: Nephrogenic syndrome of inappropriate an-
70. Mathai JC, Zeidel ML: Measurement of water and solute per- tidiuresis. N Engl J Med 352: 18841890, 2005
meability by stopped-flow fluorimetry. Methods Mol Biol 400: 88. Waikar SS, Mount DB, Curhan GC: Mortality after hospitalization
323332, 2007 with mild, moderate, and severe hyponatremia. Am J Med 122:
71. Zeidel ML: Low permeabilities of apical membranes of barrier 857865, 2009
epithelia: What makes watertight membranes watertight? Am J 89. Anderson RJ, Chung HM, Kluge R, Schrier RW: Hyponatremia:
Physiol 271: F243F245, 1996 A prospective analysis of its epidemiology and the pathogenetic
72. Rivers R, Blanchard A, Eladari D, Leviel F, Paillard M, Podevin role of vasopressin. Ann Intern Med 102: 164168, 1985
RA, Zeidel ML: Water and solute permeabilities of medullary 90. Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD: Mortality and
thick ascending limb apical and basolateral membranes. Am J serum sodium: Do patients die from or with hyponatremia? Clin J
Physiol 274: F453F462, 1998 Am Soc Nephrol 6: 960965, 2011
73. Gensure RH, Zeidel ML, Hill WG: Lipid raft components cho- 91. Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita
lesterol and sphingomyelin increase H1/OH- permeability of S: Differential expression patterns of claudins, tight junction
phosphatidylcholine membranes. Biochem J 398: 485495, membrane proteins, in mouse nephron segments. J Am Soc
2006 Nephrol 13: 875886, 2002
74. Tristram-Nagle S, Kim DJ, Akhunzada N, Kucerka N, Mathai JC, 92. Maunsbach AB, Marples D, Chin E, Ning G, Bondy C, Agre P,
Katsaras J, Zeidel M, Nagle JF: Structure and water permeability Nielsen S: Aquaporin-1 water channel expression in human
of fully hydrated diphytanoylPC. Chem Phys Lipids 163: 630 kidney. J Am Soc Nephrol 8: 114, 1997
637, 2010
75. Agre P: Homer W. Smith award lecture. Aquaporin water chan- Published online ahead of print. Publication date available at www.
nels in kidney. J Am Soc Nephrol 11: 764777, 2000 cjasn.org.