Institut de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland
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ABSTRACT |
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The epithelial
Na+ channel (ENaC) controls the
rate-limiting step in the process of transepithelial
Na+ reabsorption in the distal
nephron, the distal colon, and the airways. Hereditary salt-losing
syndromes have been ascribed to loss of function mutations in the -,
-, or
-ENaC subunit genes, whereas gain of function mutations
(located in the COOH terminus of the
- or
-subunit) result in
hypertension due to Na+ retention
(Liddle's syndrome). In mice, gene-targeting experiments have shown
that, in addition to the kidney salt-wasting phenotype, ENaC was
essential for lung fluid clearance in newborn mice. Disruption of the
-subunit resulted in a complete abolition of ENaC-mediated Na+ transport, whereas knockout of
the
- or
-subunit had only minor effects on fluid clearance in
lung. Disruption of each of the three subunits resulted in a
salt-wasting syndrome similar to that observed in humans.
hypertension; pseudohypoaldosteronism; transgenic mice
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INTRODUCTION |
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THE EPITHELIAL SODIUM CHANNEL (ENaC) is a membrane
protein made of three different but homologous subunits (,
, and
) present in the apical membrane of epithelial cells of the distal
nephron (cortical and medullary collecting tubule) and distal colon and in the airways and in the excretory ducts of several glands. It provides a controlled entry pathway for
Na+ from the lumen of these organs
into the epithelial cells, and, together with the
Na+-K+-ATPase
located in the basolateral membrane of the same cells, it is
responsible for the active, vectorial transport of
Na+ from the external medium
through the epithelial cells into the extracellular fluid and toward
the blood (7, 12).
The ENaC has different functional roles in various organs in which it is expressed. In the kidney (collecting tubule), the modulated reabsorption of Na+ through ENaC provides the primary mechanism of the regulation of urinary Na+ excretion and thus allows the fine control of the whole organism Na+ balance under the hormonal control of aldosterone. By its depolarizing effect on the apical membrane potential, the Na+ channel also provides the driving force for tubular K+ secretion. Specific inhibitors of ENaC promote urinary Na+ excretion and inhibit K+ secretion; these drugs (amiloride, triamterene) are therefore used as K+-sparing diuretics. ENaC has a similar functional role in the distal colon, preventing excessive Na+ loss in the stools. In airways, a most important role is the reabsorption of the fluid that fills the airways at birth, promoting the shift from fluid secretion (before birth) to fluid reabsorption (postnatal). With the cystic fibrosis transmembrane conductance regulator, it also participates in the delicate regulation of the fluid balance in the airways that maintains a thin mucosal fluid film necessary for mucus clearance (31). In the excretory ducts of salivary and sweat glands, the activity of ENaC tends to decrease the luminal Na+ concentration, allowing the excretion of a less salty saliva and preventing major loss of Na+ in the sweat fluid.
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MUTATIONS IN HUMAN ENAC SUBUNIT GENES |
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The pathophysiological consequences of the mutations known in humans are essentially related to the role of ENaC in the kidney and less to the role in other organs, probably because of the predominant function of ENaC in renal Na+ and K+ excretion and possibly because of partial redundancy with other Na+ transport systems in other organs (although no data are available to support this last point). Mutations of the ENaC subunit genes are responsible for two syndromes that have different effects on channel function. Mutations resulting in a decrease or loss of function result in urinary salt loss and decreased capacity to secrete K+ in urine, whereas mutations resulting in gain of function produce Na+ retention, hypertension, and excessive K+ urinary loss resulting in hypokalemia.
Mutations causing a reduced ENaC activity.
Pseudohypoaldosteronism type 1 (PHA-1) is a heterogenous clinical
syndrome characterized by mineralocorticoid end organ resistance, i.e.,
urinary loss of Na+ and reduced
K+ excretion despite an elevated
level of aldosterone (18). A severe form of this syndrome is inherited
as an autosomal recessive trait, results in sometimes lethal episodes
of hyponatremia, hypotension, and hyperkalemia, and shows alteration of
Na+ transport in several organs,
kidney, salivary glands, sweat glands, and colon (11). In several
families showing this form of PHA-1, links to mutations in any one of
the three ENaC subunits (5, 30) were found, as shown in Fig.
1. A causal link between these mutations
and the PHA-1 syndrome was further supported by the demonstration that
these mutations resulted in decreased ENaC activity in an artificial
expression system (8). A less severe form of PHA-1 with an autosomal
dominant mode of inheritance is symptomatic mostly during infancy and
improves with age (17).
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Gain of function mutations.
Liddle's syndrome, an autosomal dominant hereditary form of
hypertension, is characterized by an early and severe hypertension, often accompanied by metabolic alkalosis and hypokalemia (19), all
signs that are characteristic of an excess of aldosterone (Conn's
syndrome). The plasma level of aldosterone is however low. For this
reason, Liddle's syndrome is also called pseudoaldosteronism. This
severe form of hypertension is remarkably responsive to treatment with
a low-salt diet and Na+ channel
inhibitors (K+-sparing diuretics),
suggesting a primary defective regulation of the ENaC. Indeed, linkage
studies showed that this trait was due to mutations in the genes of
ENaC subunits (28). As illustrated in Fig. 1, these mutations are all
localized in the COOH-terminal region of the -subunit (10, 15, 16,
28, 32) and
-subunit (9, 30). Furthermore, these mutations all
modify the so-called "PY" motif (the consensus sequence PPXY, see
Fig. 1) either by missense mutations, by introduction of an upstream
frameshift, or by a stop codon that results in elimination of the PY
motif. In expression systems, these mutations have been shown to result in the overexpression of Na+
channels that are hyperactive compared with the wild-type ENaC (25,
26). More precisely, Kellenberger et al. (17) have shown that these
mutations prevent the downregulation of the channel that normally
occurs with a rise in intracellular
Na+: ENaC channels bearing the
Liddle's mutation remain in a highly active state despite a high
intracellular Na+ concentration.
The mechanism of this downregulation is not yet completely elucidated
but may involve the binding of the ubiquitin ligase Nedd-4 through a
direct interaction of the PY motif in the COOH terminus of ENaC
subunits with the WW domain of Nedd-4 (29) and/or
clathrin-mediated endocytosis (27).
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TRANSGENIC MOUSE MODELS WITH ALTERED ENAC FUNCTION |
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Both the loss of function and the gain of function mutations in ENaC
genes are extremely rare in humans, and no homologous spontaneous
mutations are known in animals. It is therefore very difficult to study
the pathophysiology of these diseases. However, mutant animals provide
a means to explore in detail the consequences of these mutations in a
living organism. The deletion or modification of ENaC subunits in vivo
would show possible functional redundancy and requirements of different
ENaC subunits for its functional role in different organs. Thus the
relative importance of each ENaC subunit is now experimentally testable
in animal models, and mouse models bearing mutations in all three
subunits (-,
-, and
-ENaC) have been generated that result in
reduced or complete abolishment of ENaC activity (2, 13, 21). This allows us to address the questions of how much ENaC activity is sufficient to maintain Na+ balance
or pulmonary fluid balance in vivo. As described below and summarized
in Table 1, reduced ENaC
activity in these (ENaC-mutant) mice leads to clinical symptoms similar
to the PHA-1 phenotype, ranging from mild to severe forms of this
disease.
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Inactivation of the -ENaC subunit gene locus.
Inactivation of the mouse
-ENaC gene locus demonstrated that
-ENaC is indispensable for lung liquid clearance at birth. Absence
of ENaC function, in
-ENaC(
/
) mice, led to a
respiratory distress syndrome and neonatal death (13). The
amiloride-sensitive electrogenic
Na+ transport in airway epithelia
was completely abolished, indicating that without
-ENaC no
functional Na+ channels are
expressed. Furthermore, the newborns showed metabolic acidosis with
significantly lower blood pH and HCO
3 concentrations. Unfortunately, these mice die so early that it is
impossible to evaluate either the extent of electrolyte disturbances or
the epithelial function in kidney and colon. Using a transgenic approach, we therefore attempted to rescue the
-ENaC deficiency by
reintroducing the rat
-ENaC cDNA under the control of an
heterologous (cytomegalovirus) promoter. The function induced by the
transgene in the airways was sufficient to alleviate the respiratory
distress syndrome, and about one-half of the transgenic (Tg) animals
survived to adult age. Surviving
-ENaC(
/
)Tg mice
developed a PHA-1 with growth retardation, prominent salt-wasting in
the first weeks of life, and metabolic acidosis (14). The 50% early
mortality in
-ENaC(
/
)Tg mice also demonstrated that
the neonatal period is quite sensitive to electrolyte disturbances, as
observed in mice deficient for the mineralocorticoid receptor (MR) (3). Adult
-ENaC (
/
)Tg mice escaped from this severe
PHA-1, and their metabolic profile changed with age. In these animals,
blood gases and serum and urinary electrolyte concentrations were in the normal range despite plasma aldosterone levels that were elevated sixfold (14), suggesting that these animals were constantly hypovolemic. This course of the disease is similar to that of patients
with PHA-1, in which supplementary
Na+ requirements diminish over
time. The mechanism of this adaptation to distal nephron
Na+ loss is not yet well
understood (23). Redundant mechanisms of salt transport may be
relatively more efficient in the kidney, colon, and lung of adults.
Disruption of the -ENaC gene in mice.
A mutation was introduced into the mouse
-ENaC gene locus, which led
to low
-ENaC RNA levels (<4%) and absence of detectable
-ENaC
protein (21). With normal salt intake, these mice, designated as
-ENaC(m/m), showed normal growth rates, no respiratory phenotype, but exhibited a lower Na+
transport in colon. Urinary Na+
and K+ concentrations were
elevated, and the mice showed a mild PHA-1 with compensated metabolic
acidosis and slightly elevated plasma aldosterone levels. With low-salt
diet (0.1 g Na+/kg dry food),
these mice developed clinical symptoms of an acute PHA-1 with
continuous weight loss, hyperkalemia, and decreased blood pressure
(21). Thus, under certain conditions, like low-salt intake, there was a
failure of ENaC function because of the absence or low amount of
-ENaC, even though in colon Na+
transport measured as the amiloride-sensitive potential difference (PD) was increased. This indicates that the
-ENaC
subunit is required for a full Na+
conservation capacity during salt deprivation.
Inactivation of the -ENaC gene locus.
In mice, inactivation of the
-ENaC subunit resulted in early death
of homozygous
-ENaC knockout mice at ~36 h after birth. The death
was mainly caused by severe disturbances of
Na+ and
K+ balance (2). Shortly after
birth, these mice exhibited a severe neonatal PHA-1 syndrome with
urinary Na+ wasting, low urinary
K+ excretion, and a large increase
in plasma K+ concentration.
Surprisingly, these
-ENaC knockout mice did not present any
respiratory distress syndrome.
Mouse models with reduced ENaC activity.
Mice heterozygous for an inactivating mutation in the -,
-, or
-ENaC subunit are expected to produce 50% of RNA transcripts from
the corresponding gene but do not show obvious clinical symptoms of
PHA-1. They exhibit normal blood
Na+,
K+ and
HCO
3 concentrations and pH values, and urinary electrolytes are in the normal range. Although measurements of
amiloride-sensitive short-circuit current in airway epithelia showed
nearly normal ENaC-mediated Na+
transport, in vivo measurements of amiloride-sensitive transepithelial PD in colon (
PDamil) showed
up to 50% reduction in ENaC activity in
- and
-ENaC heterozygous
mutant mice (2, 21). In
-ENaC heterozygous mutant mice, mean values
of PDamil were not different from
wild-type mice, but the normally observed diurnal cyclicity of
PDamil was abolished (33).
However, treatment with an ANG II receptor blocker (irbesartan) reduced
mean blood pressure in
-ENaC(+/
) mice, indicating that
Na+ balance and blood pressure
were maintained possibly as a result of an increased responsiveness to
ANG II (34). This might represent a compensatory mechanism to a partial
deficit of
-ENaC expression in heterozygous knockout animals.
Mouse models with dysfunction in the regulation of ENaC activity.
In the distal nephron, ENaC activity is highly dependent on
mineralocorticoid stimulation. Not surprisingly, cases of PHA-1 syndrome have been ascribed to alteration of the MR gene (1), and mice
in which the MR receptor was inactivated developed severe symptoms of
PHA with failure to thrive, weight loss, severe
Na+ and water loss, and a highly
stimulated renin-ANG system (3). These MR(/
) mice die
around 10 days after birth because they are not able to compensate for
Na+ loss. Interestingly,
amiloride-sensitive Na+ absorption
is reduced, but the abundance of the mRNAs encoding for ENaC and
Na+-K+-ATPase
subunits is unchanged, indicating that regulation of
Na+ absorption via MR is not
achieved by transcriptional control of ENaC and
Na+-K+-ATPase.
Daily injections of the glucocorticoid betamethasone from
day 5 after birth onward prolonged
survival of MR(
/
) mice but could not completely replace
MR function. In lung, ENaC transcription is controlled by
glucocorticoids (22), and inactivation of the glucocorticoid receptor
in vivo resulted in perinatal death due to respiratory failure (6);
lung maturation was severely retarded, and the abundance of mRNA
encoding the amiloride-sensitive ENaC was diminished.
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PERSPECTIVE |
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Gene-targeting experiments have already unveiled some of the mechanisms
underlying the control of Na+
balance and blood pressure regulation. Animals deficient in genes can
be readily intercrossed to explore their functional relationship. Transgenic expression of the enzyme Cre recombinase can induce tissue-specific gene targeting, resulting in selective
reactivation or inactivation of the gene (22, 24). These new strategies can be used to overcome lethal phenotypes (e.g., in - and
-ENaC knockout mice) and to study tissue-specific functions of ENaC at any
given time during development or adulthood. The engineering of new
animal models based on mutations identified in humans will provide
novel opportunities to examine the effect of particular mutations in
different defined environments and to explore the physiological
consequences of different combinations of mutant genes.
In summary, the ENaC has been shown to be essential in the vital function of Na+ balance regulation by the kidney and colon and in the control of fluid balance in the airways. Its role and physiology in colon and exocrine glands are only starting to be understood. Experiments in mutant mice will allow reproduction of human monogenic hereditary diseases, and this approach gives us the possibility to acquire a much better understanding of the pathophysiology of these disorders. The combination of gene-targeting and classical transgenic approaches will therefore prove very useful in elucidating the implication of ENaC in more complex, but more frequent, multifactorial traits such as the genetic predisposition to hypertension.
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ACKNOWLEDGEMENTS |
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We are grateful to B. C. Rossier for continuous support on this project.
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FOOTNOTES |
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* Fifth in a series of invited articles on Genetic Disorders of Membrane Transport.
Our work in this field is supported by the Swiss Fonds National de la Recherche Scientifique (grants 31-43384.95 and 31-52943.97, E. Hummler) and by the International Human Frontier Science Program Grant RG-464/96 (J.-D. Horisberger).
Address for reprint requests: J.-D. Horisberger, Institut de Pharmacologie et de Toxicologie, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland (E-Mail: Jean-Daniel.Horisberger{at}ipharm.unil.ch).
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