Departments of Physiology and Biophysics, and Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
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ABSTRACT |
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Although the aldosterone-responsive
segments of the nephron together reabsorb <10% of the filtered
Na+, certain single-gene defects that affect the epithelial
Na+ channel (ENaC) in the luminal membrane of the
collecting duct (CD) or its regulation by aldosterone cause severe
hypertension, whereas others cause salt wasting and hypotension. These
rare defects illustrate the key role of the distal nephron in
maintaining normal extracellular volume and blood pressure. Genetic
defects that increase the Cl conductance of the
junctional complexes may also lead to salt retention and hypertension.
Less dramatic alterations in regulatory actions of other hormones such
as vasopressin (VP), either alone or with other genetic variations,
diet, or environmental factors, may also produce Na+
retention or loss. Although VP acts primarily to regulate water balance, it is also an antinatriuretic hormone. Elevated basal plasma
VP levels, and/or augmented VP release with increased Na+
intake, have been linked to essential hypertension in humans and in
animal models of congestive heart failure and cirrhosis. Norepinephrine, dopamine, and prostaglandin E2 can inhibit
the antinatriuretic effects of VP, and changes in the actions of these autocrine and paracrine regulators may also be involved in abnormal regulation of Na+ reabsorption.
cortical collecting duct; medullary collecting duct; distal convoluted tubule; sodium balance; potassium balance; vasopressin; aldosterone; gene defects; hypertension; sodium transport; potassium transport; chloride transport; epithelial sodium channel
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INTRODUCTION |
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BECAUSE THIS REVIEW FOCUSES on the regulation of epithelial Na+ channels (ENaC) in the collecting duct (CD), other nephron segments and organ systems that can be important contributors to extracellular fluid (ECF) volume and blood pressure regulation have been neglected. Thus the reader may conclude incorrectly that the kidney alone, or more specifically the cortical collecting duct (CCD) alone, is responsible for abnormalities in these processes. However, even in the case of salt-sensitive hypertension, there is a large body of evidence from animal and human studies that defects in the central control of the sympathetic nervous system may play an important role (45, 145). It is perhaps even more important to dispel any false perception that the rare genetic disorders discussed below may be important contributors to more common forms of human hypertension. While these disorders do demonstrate that single molecular defects that interfere with the regulation of renal Na+ excretion are sufficient to produce hypertension, there is no evidence that they are necessary components of essential hypertension. However, such single-gene defects do provide impressive (and relatively uncomplicated) links among molecules, physiological systems, and pathology, and they turn our attention to associated regulatory mechanisms that may be involved in essential hypertension.
The role of ECF volume in the control of arterial blood pressure, and hence the role of the kidneys vs. the cardiovascular system in hypertension and edematous states such as congestive heart failure, have been matters of controversy for decades. Using parameters and relationships derived from animal studies, Guyton (46, 47) proposed a dominant role for the kidneys based on a mathematical model of the interactions among the multiple organ systems that determine ECF volume and blood pressure. They showed that, because of the rapid response of baroreceptor reflexes, acute changes in ECF volume produced little change in blood pressure. In contrast, chronic changes in ECF volume could only be corrected by increased Na+ and water excretion, which were determined by a feedback mechanism with an apparent "infinite gain." Guyton described the relationship between blood pressure and renal Na+ excretion in terms of renal function curves, which predicted that when Na+ excretion is impaired, blood pressure rises until the resulting pressure natriuresis achieves Na+ balance (46, 47).
Many of the predictions of the Guyton model have been confirmed in humans (e.g., see Ref. 67). Arguably, however, the best support has come from the identification of molecular defects linked to heritable forms of hypertension and salt wasting and from the explanations of the pathophysiology of those disorders. As a consequence of previous physiological studies that provided the fundamental information about the location and regulation of ion and water transporters in the nephron, certain single-gene defects have been shown to produce renal salt retention and hypertension, whereas other defects lead to salt wasting and hypotension. Consequently, these defects support the primacy of the kidneys in ECF volume regulation predicted by the Guyton model.
For the most part, these single-gene defects affect Na+ reabsorption in those segments of the nephron that express the mineralocorticoid receptor (MR), i.e., the distal convoluted tubule (DCT), the connecting tubule (CNT), and CD (10, 27). The DCT and CCD respond to aldosterone with increased Na+ reabsorption and K+ secretion, and, although the evidence is sparser (see below), aldosterone may produce the same effects in the CNT and portions of the medullary CD. This review, however, concentrates on the CCD, in which Na+ reabsorption is mediated primarily, if not exclusively, by ENaC.
In the DCT, Na+ reabsorption occurs via the
thiazide-sensitive NaCl cotransporter (NCCT; also known as NCC or TSC;
OMIM no. 600968; for references, see Ref. 96) in the
luminal membrane.1 However,
the DCT is difficult to characterize because it is composed of multiple
subsegments with different cell types within which the distribution of
transporters and associated enzymes varies markedly among species (for
an excellent editorial comment, see Ref. 136). ENaC
appears to have no functional role in the DCT, although expression of
ENaC subunits is variably found in the CNT and DCT (76,
133). In the DCT, the distributions of MR and the enzyme
11-hydroxysteroid dehydrogenase type 2 (11
-HSD2; see below) are
also quite variable among subsegments and species (10, 27, 96,
136). Finally, vasopressin (VP) has no action in the DCT, which
lacks the necessary V2 receptors.
Some subsegments of the DCT respond to aldosterone (probably in combination with glucocorticoids; see Refs. 96 and 136) with increased K+ secretion and Na+ reabsorption due to de novo synthesis of NCCT, and increased Na+ delivery to the DCT enhances this effect (66, 96). Thus the DCT contributes to Na+ retention or wasting in those disorders involving the synthesis or actions of aldosterone and other adrenal corticosteroids. Furthermore, at least one gene defect resulting in altered Na+ balance, the Gitelman's syndrome (a variant of Barrter's syndrome; OMIM no. 263800), is confined to the DCT. In this disorder, various mutations in the NCCT gene result in a loss of function, and thus salt wasting, which is accompanied by hypocalciuria, and K+ and Mg2+ depletion (114).
This review also neglects the medullary CD, which, like the DCT, is
quite heterogeneous (123). Although MR, 11-HSD2, and all three ENaC subunits are present in outer and inner medullary CD
segments (10, 27, 48, 133), the actions of aldosterone appear to be confined primarily to the CCD (123). For
these reasons, this review focuses on the CCD, but the possibility that
some of the same mechanisms are involved in the medullary CD should be
kept in mind.
It may at first seem quite remarkable that, despite the fact that the aldosterone-responsive segments of the nephron in combination reabsorb <10% of the filtered load of Na+, regulatory defects in the control of that reabsorption result in marked changes in body Na+ balance and blood pressure. These consequences appear to be disproportionate to the amount of Na+ reabsorbed; however, as argued cogently by Schnermann (110), relatively gross abnormalities in Na+ and water reabsorption in the more proximal regions of the nephron are offset by changes in the glomerular filtration rate due to tubuloglomerular feedback, but this mechanism does not respond to changes in salt and water delivery beyond the macula densa.
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CCD ION TRANSPORTERS |
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Figure 1 illustrates the primary
transporters involved in Na+ reabsorption and
K+ secretion in the CCD. Microelectrode and patch-clamp
studies in isolated, perfused CCD segments (e.g., 37, 38, 88, 100, 109), as well as in planar epithelia and cell cultures derived from or
resembling the CCD, established the general characteristics of the
apical Na+ channel, especially its high selectivity to
Na+ and its inhibition by low concentrations of amiloride
(42, 134). Mechanisms regulating the activity of this ENaC
have been the subject of intensive study since the cloning and
sequencing of its three component subunits, -,
-, and
-ENaC,
by Canessa et al. (14, 16). All three have two
transmembrane regions connected by an extracellular loop, with both
NH2- and COOH-terminal regions on the cytoplasmic side of
the membrane. Although the stoichiometry of
-,
-, and
-subunits that comprise a functional channel remains controversial,
the identification of an ENaC complex as the mediator of
amiloride-sensitive Na+ entry (42, 134) has
provided a wealth of information concerning the normal and abnormal
regulation of Na+ transport in the CCD.
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As is the case throughout the nephron and similar epithelia, the motive force for Na+ and K+ transport by the CD is the ubiquitous Na+-K+-ATPase, and it is activated by aldosterone, although only in the presence of increased Na+ entry (8, 90). Thus it appears that the primary regulation of Na+ reabsorption by aldosterone occurs by changes in ENaC activity, which is the rate-limiting step in transepithelial transport, and that there is no increase in Na+-K+-ATPase activity unless there is apical Na+ entry (90).
Under most conditions, K+ transport across the apical membrane of the CCD is mediated by ROMK1 (also called SK) channels that may be regulated somewhat differently than those in the thick ascending limb (86, 87). However, as with other ROMK channels, these channels are inwardly rectifying, inhibited by ATP, and have a low unit conductance (25-40 pS). In addition to ROMK1, K+ secretion across the apical membrane of the CCD is also mediated by maxi-K (or BK) channels, so named for their high unit conductance (80-140 pS), which may be activated by elevated intracellular calcium concentration ([Ca2+]i) and membrane stretch (36, 58, 87, 107). Under the usual experimental conditions, the maxi-K+ channels are inactive (81), but they may be activated by cell swelling and increased luminal flow (54, 144). The basolateral membrane conductance is dominated by both low (~30-pS)- and intermediate (~80-pS)-conductance K+ channels (55, 56, 81, 138).
The mechanism for Cl reabsorption in the CCD has been
neglected relative to the cations, an oversight that will be addressed in more detail below. Electrophysiological studies in the rabbit CCD
established that there is a substantial Cl
conductance in
the basolateral membrane that under some conditions may exceed the
K+ conductance (82, 85, 100, 101). Although
the CLC-K family of channels, members of which are expressed in many
segments of the nephron, might seem to offer the best candidates, only
CLC-K2 has been found in the CCD, and only in the basolateral membranes of A-type intercalated and not principal cells (68). In
their study of the basolateral Cl
channel, Sansom et al.
(101) could find no evidence for an apical conductance and
suggested that an electroneutral anion exchanger might mediate apical
Cl
transport. Although the anion exchanger AE2 was
previously thought to be expressed only in intercalated cells, more
recent observations in primary cultures of rabbit CCD cells also
demonstrated AE2 in principal cells (30).
Figure 2A illustrates the
putative transcellular route for Cl reabsorption in the
rabbit CCD. However, even in the rabbit CCD, a substantial fraction of
transepithelial Cl
transport occurs paracellulary through
the junctional complexes and is driven by the lumen negative
transepithelial voltage (139), as depicted in Fig.
2B. In the rat CCD, paracellular diffusion appears to be the
sole possible route for Cl
reabsorption because no
Cl
conductance could be found in either the apical or
basolateral membranes (108).
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REGULATION OF NA+ Transport by Aldosterone |
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The primary hormonal regulator of Na+ reabsorption and K+ secretion in the CD and similar epithelia is aldosterone, which induces the transcription of specific genes via the MR, and hence, the synthesis of "aldosterone-induced proteins" (AIPs). The ultimate results of this change in transcription include increased ENaC-mediated Na+ conductance of the apical membrane, increased activity of Na+-K+-ATPase in the basolateral membrane, and increased levels of mitochondrial enzymes such as citrate synthase (41, 42, 98, 134).
Despite general agreement about the ultimate actions of aldosterone, the identity of the "proximate" AIPs, i.e., the proteins, the expression of which is directly elevated by the MR, has been elusive. The most promising candidate in the CD is a serine-threonine kinase that was initially characterized as being activated by serum and glucocorticoids (SGK; also variably referred to as SGK1 or sgk). Differential gene expression techniques in A6 cells (21) and primary cultures of rabbit CCD cells (83) indicate that SGK is a proximate AIP. Aldosterone increases SGK mRNA within 30 min in these cells as well as in the M-1 mouse CCD cell line and in the rat CCD in situ (21, 76, 83, 89, 111). Because coexpression of SGK with the three ENaC isoforms in Xenopus laevis oocytes produced much higher amiloride-sensitive currents than the injection of mRNA for the ENaC subunits alone, SGK activation appears to be coupled to increased ENaC activity independently of any changes in subunit expression (21, 83, 89, 111).
Rather than phosphorylating ENaC subunits themselves, SKG appears to
phosphorylate other proteins that are involved in the trafficking of
ENaC into and retrieval from the cell membrane. Alterations in the
rates of insertion and retrieval are envisioned as determining the
density of ENaC in the apical membrane, as depicted in Fig.
3. Attention has focused recently on the
retrieval pathway in which the binding of ubiquitin to specific
membrane proteins leads to their internalization and degradation by
proteosomes. Several studies have shown that the WW domain of the
ubiquitin ligases Nedd1-1 and Nedd4-2 bind specifically to a
"PY domain" (PPPXY) that is present in the cytoplasmic
COOH-terminal regions of all three ENaC subunits and that the binding
of these ligases decreases ENaC activity (29, 50, 64, 65, 115,
118-120). This evidence has been reconciled with the action
of SGK in the model shown in Fig. 4,
which is based on the very recent studies of Debonneville et al.
(24) and Snyder et al. (116). These investigators showed that SGK binds to and phosphorylates Nedd4-1 and/or Nedd4-2. This phosphorylation was found to reduce
Nedd4-2 affinity for one or more of the ENaC subunits (24,
116). With diminished Nedd4 activity, less ENaC is
ubiquitinylated, internalized, and degraded. Thus the model predicts
that aldosterone, by inducing SGK as a proximate AIP, leads to ENaC
channel accumulation in the membrane.
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In the late phase of aldosterone action (after several hours), there is
increased synthesis of both ENaC subunits and
Na+-K+-ATPase that probably represents
secondary effects of the proximate AIPs. Although there appear to be
cis elements that are activated by aldosterone and
dexamethasone in the 5'-flanking region of the -ENaC gene
(79), aldosterone produces only a modest increase in
-ENaC mRNA and protein and no changes in
- and
-ENaC in the
rat and mouse CCD (76-78, 125). There is also no
association between aldosterone deficiency and the expression of ENaC
subunits. Berger et al. (7) showed there was no decrease
in ENaC subunit mRNA expression in mice in which the MR receptor had
been knocked out despite their greatly increased fractional
Na+ excretion. Despite the fact that aldosterone has little
effect on ENaC abundance, it does enhance the migration of ENaC into the apical membrane (48, 75, 76, 78).
Methylation of ENaC may also be a component of the response to
aldosterone that occurs before any increases in ENaC or
Na+-K+-ATPase synthesis (121). In
detached patches from A6 cells, application of a substrate for protein
methyltransferase increased the open probability of single ENaC
channels, and -ENaC has been shown to be directly methylated in
studies with the in vitro translated protein in lipid bilayers and in
intact A6 cells, and this methylation increases channel activity
(59, 97). The most puzzling aspect of methylation as an
early aldosterone effect has been the failure to show any increase in
the levels of methyltransferase proteins despite their increased
activity. It appears that these proteins are not regulated at the
transcriptional or translational level but through posttranslational
modification by a proximate AIP (121).
Although aldosterone activation of SGK and transmethylases occurs within 30 min and well before any synthesis of new ENaC or Na+-K+-ATPase subunits, mounting evidence suggests that aldosterone and other steroid hormones have even more rapid initial effects that involve membrane receptors coupled to the activation of the phospholipase C (PLC) signaling system and elevation of [Ca2+]i (26). In patch-clamp studies of isolated rabbit CD principal cells, Zhou and Bubien (152) have shown that aldosterone increases ENaC activity within 2 min. This effect was not prevented by the MR blocker spironolactone but was completely inhibited by amiloride.
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DEFECTS IN THE REGULATION OF CCD NA+ Transport Leading to Volume Expansion |
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Syndromes of abnormal Na+ retention by the CD that
result in the expansion of ECF fall into two basic classifications of
etiology, all of which are characterized by severe hypertension,
hypokalemia, and, to a more variable degree, alkalosis, as depicted in
Fig. 5. The first group includes those
conditions in which there is an excess of mineralocorticoid activity
due to either aldosterone overproduction or abnormal steroid
metabolism. A primary example is the long-used experimental model of
hypertension produced by exogenous DOC in combination with elevated
dietary salt (43). The second group consists of mutations
in the genes encoding the ENaC subunit that result in a gain of
function and/or loss of their regulation, which are now collectively
referred to as Liddle's syndrome.
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In all of these conditions, excessive K+ secretion accompanies the accelerated Na+ reabsorption. As shown in Fig. 1, the lumen negative voltage in the CCD is a consequence of the depolarization of the luminal membrane produced by the ENaC channels, and it is augmented by increased ENaC activity. Microelectrode studies in the CCD have shown that this increased driving force is sufficient to account quantitatively for the stimulation of K+ secretion by aldosterone and VP in the rat CCD (105), and patch-clamp studies have shown no effect of short-term aldosterone administration on K+ channel density (87). In the rabbit CCD, however, aldosterone also increases the K+ conductance of the apical membrane (69, 100). Thus the K+ wasting with Liddle's syndrome or excess mineralocorticoid activity is a secondary consequence of the depolarization of the apical membrane, possibly accompanied by increased ROMK activity in the case of the latter etiology.
Syndromes of mineralocorticoid excess are seldom related to abnormalities of the hypothalamic-anterior pituitary axis, because ACTH exerts little or no control over aldosterone secretion. Primary aldosteronism (Conn's syndrome; see OMIM no. 103900) is the unregulated and augmented secretion of aldosterone due to bilateral hyperplasia of the adrenal cortex or an aldosterone-producing adrenal adenoma. Excessive aldosterone production can also be driven by an appropriate response to aberrant activation of the renin-angiotensin system, in which case it is referred to as secondary aldosteronism. Another cause of aldosterone overproduction is an autosomal dominant disorder produced by a chimeric gene duplication event that results in aldosterone synthase expression driven by an abnormal promoter that responds to ACTH (74). The condition can be treated by glucocorticoid therapy (which suppresses ACTH release), and thus it is referred to as glucocorticoid-remediable aldosteronism (GRA; also known as GSH or familial hyperaldosteronism type I; OMIM no. 103900).
Under some circumstances, glucocorticoids may produce mineralocorticoid
actions. For example, when glucocorticoids are given therapeutically,
retention of salt and water is a common side effect. A more interesting
example in the present context is the autosomal recessive genetic
disorder of apparent mineralocorticoid excess (AME; alternatively, AME1
or AME2; see OMIM nos. 218030 and 207765). The range of plasma cortisol
concentrations in man is >100-fold higher than that of aldosterone,
yet the affinities of these hormones for MR are similar, and thus
glucocorticoids could cause excessive mineralocortidoid actions
(27). This normally does not occur because the
aldosterone-sensitive regions of the nephron express the enzyme
11-HSD2 (also called HSD11B2; OMIM no. 217030), which converts
circulating cortisol to cortisone. Because cortisone does not activate
the MR, the enzyme effectively "protects" these receptors from
occupancy by glucocorticoids (27, 40). In AME, deficient
11
-HSD2 activity allows cortisol to exert the same effects as excess
aldosterone (27). Several different mutations in the
11
-HSD2 gene are known to reduce or eliminate its activity, and this
polymorphism may account for variability of the phenotype that has led
to categorization as types I and II AME (OMIM nos. 218030 and 207765, respectively).
Since the molecular identification of the amiloride-sensitive
Na+ channel in the CCD as a heterotrimeric assembly of ENaC
subunits, there has been renewed interest in Liddle's syndrome (Fig.
5). Liddle's syndrome [also known as pseudoaldosteronism (PHA); OMIM no. 177200] is a rare autosomal dominant disorder that resembles primary aldosteronism but with no elevation of aldosterone and no
amelioration by glucocorticoids as found in AME. In the original kindred, the disorder was shown to be linked to a mutation in the
-ENaC gene that results in truncation of the cytoplasmic COOH-terminal region of the protein (112). These
observations stimulated a worldwide search for other kindreds in which
low-renin hypertension might be associated with ENaC mutations.
Multiple kindreds exhibiting Liddle's syndrome have been identified
with autosomal dominant linkage to a variety of mutations in the
COOH-terminal region of
-ENaC, including missense, nonsense, and
truncation mutations (49, 62, 122, 132), and a single
kindred with truncation of the cytoplasmic COOH-terminal domain of
-ENaC (49).
The evidence associating Nedd4 and the ubiquitin degradation system
with ENaC regulation has provided a compelling explanation for the gain
of function of ENaC in Liddle's syndrome. As can be seen in Fig. 4,
truncation of the COOH-terminal region or mutations that disrupt its
PPPXY motif would prevent Nedd4 binding and ubiquitin-mediated internalization of the mutant ENaC. Staub et al.
(119) proposed this mechanism as the basis of Liddle's
syndrome; i.e., defective internalization of ENaC subunits would lead
to an increase in their steady-state level in the apical membrane
independently of aldosterone regulation. This hypothesis is supported
by observations that the introduction of Liddle mutations in the -
and
-ENaC subunits expressed in X. laevis oocytes and
Madin-Darby canine kidney cells increases amiloride-sensitive transport
and the surface density of ENaC channels (34, 117).
The association between Na+ retention and hypertension is further supported by experiments in transgenic mice expressing the Liddle trait. Mice that are heterozygous or homozygous for the Liddle mutation develop normally during the first 3 mo of life but exhibit low plasma aldosterone consistent with chronic hypervolemia. When given a high-salt diet, the mice rapidly develop hypertension, hypokalemia, and metabolic alkalosis (91).
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DEFECTS IN THE REGULATION OF CCD NA+ Transport Leading to Volume Contraction |
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Disorders associated with renal Na+ wasting and
extracellular volume contraction that often lead to hypotension are
effectively the mirror image of those producing volume contraction. As
outlined in Fig. 6, they can be
categorized as disorders in which aldosterone production is impeded or
its action is prevented, or there are loss-of-function mutations in
ENaC subunits. Disorders in both categories are associated with salt
wasting, hyperkalemia, and variable acidosis. Hyperkalemia arises
because of the diminished activity of Na+ channels in the
luminal membrane, which reduces the depolarization of that membrane and
hence reduces the driving force for K+ secretion across the
luminal membrane.
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Addison disease (primary adrenocortical deficiency), which is due to
idiopathic or autoimmune destruction of the adrenal cortex, can produce
severe hypovolemia and hyperkalemia. The syndrome of PHA type I (PHA1)
is also characterized by salt wasting, hypotension, and hyperkalemia
but in the presence of high plasma renin and aldosterone. PHA1 is now
recognized to include two different and rare heritable disorders, one
being autosomal dominant and the other autosomal recessive. The
autosomal dominant form of PHA1 (OMIM no. 177735) represents a loss of
aldosterone effect in the nephron because of mutations in MR (44,
135). Autosomal recessive PHA1 (OMIM no. 264350) is caused by
loss-of-function mutations in ENaC that have been demonstrated in all
three isoforms in different pedigrees (18, 33, 126).
Interestingly, these mutations occur either in the cytoplasmic
NH2-terminal region (- and
-ENaC) or in the
extracellular loop (
- and
-ENaC) but not in the COOH-terminal region. Firsov et al. (32) expressed one of the mutant
variants of
-ENaC in X. laevis oocytes together with
wild-type
- and
-ENaC and observed proportional decreases in the
amiloride-sensitive current and the surface expression of ENaC. They
hypothesized that the mutant ENaC isoforms associated with autosomal
recessive PHA1 interfered with the normal trafficking of assembled ENaC channels to the plasma membrane.
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A ROLE FOR A CL![]() |
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All of the disorders of ECF volume regulation discussed above are
attributable to abnormalities in the regulation of Na+
transport in the aldosterone-responsive segments of the nephron, especially the CCD. A common aspect of these disorders is the reciprocal relationship between Na+ and K+
transport-augmented Na+ reabsorption being associated with
excessive K+ secretion and wasting (Fig. 5), whereas
Na+ wasting is accompanied by diminished K+
secretion and hyperkalemia (Fig. 6). This relationship might seem to be
an inescapable consequence of the electrical coupling between
Na+ reabsorption and K+ secretion due to the
depolarization of the luminal membrane produced by ENaC (Fig.
7). The apparent invariance of the
relationship between Na+ reabsorption and K+
secretion leads one to question how the CCD can be a primary regulator
of both. For example, how can the CCD increase Na+
reabsorption and decrease K+ secretion (or even produce net
K+ reabsorption) when there is a deficit of both?
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A possible explanation is that the usual assumption that the body's K+ balance is achieved primarily by aldosterone-mediated regulation of K+ secretion in the CCD is incorrect. Rabinowitz (for references, see Ref. 93) has patiently but persistently presented evidence that aldosterone is not a kaliuretic hormone at normal plasma concentrations and that marked diurnal changes in K+ excretion, or changes in excretion in response to changes in dietary intake, are not correlated with changes in plasma aldosterone or K+ concentrations. He and a group of Russian investigators (31, 92, 93) have hypothesized that the central nervous system mediates meal-induced and diurnal variations in K+ excretion. Unfortunately, the postulated K+ receptors in the gastrointestinal tract and regulatory signaling mechanism that affects the kidney have not been identified. However, even if there are mechanisms of K+ regulation other than aldosterone, they must be overwhelmed by the more extreme changes in mineralocorticoid regulation or ENaC activity summarized in Figs. 5 and 6. Indeed, Rabinowitz (92) agrees that aldosterone is kaliuretic at supraphysiological concentrations. Thus the question of whether Na+ reabsorption in K+ secretion can be dissociated at the level of the CCD remains regardless of the role of aldosterone and variations in ENaC activity in the normal regulation of K+ balance.
Intercalated cells in the CCD present a possible pathway by which the reciprocal relationship between Na+ and K+ transport might be dissociated. It has been shown that type A intercalated cells can actively reabsorb K+ via the H+-K+-ATPase (143), but is it reasonable that this transporter must be activated to counteract elevated K+ secretion by the principal cells in Na+ depletion? Another solution to dissociating Na+ and K+ transport in the CCD could involve independent regulation of the basolateral and apical K+ channels depicted in Fig. 1. One might argue that increased K+ secretion coupled to increased Na+ reabsorption would not be obligatorily if the ratio of apical (ROMK1) to basolateral K+ conductances could be regulated. Alternatively, K+ secretion might be diminished by the increase in basolateral K+ conductance that accompanies increased Na+ reabsorption (109). In either case, however, net K+ secretion would be decreased only if there were a driving force for K+ efflux from CCD cells across the basolateral membrane. The latter is questionable, especially in situations when Na+-K+-ATPase activity is stimulated, because the net K+ electrochemical potential gradient across the basolateral membrane actually favors K+ uptake (100, 109).
Once again, a congenital abnormality, PHA type II [PHA2; also known as Gordon (or familial) hypertensive-hyperkalemia; OMIM no. 145260], provides a clue to solve this apparent dilemma. The most consistent clinical characteristics of this rare autosomal dominant disorder include hyperkalemia and hypertension with normal renal function, and the exceptional amenability of the hypertension and ion imbalances to treatment with thiazide diuretics.
By a careful clinical study of one patient with this syndrome, and from
descriptions of other such patients, Schamblen et al.
(106) proposed that this disorder represents a defect in the regulation of Cl reabsorption by the distal nephron,
such that the lumen-negative driving force that normally favors
K+ secretion is diminished by an augmented Cl
conductance. As shown in Fig. 7, the lumen negative voltage, which
develops in the CCD because of the ENaC-dependent depolarization of the
luminal membrane, provides the driving force for Cl
reabsorption as well as K+ secretion. An increase in the
Cl
permeability of the junctional complexes, or the
introduction of a conductive pathway for transcellular Cl
movement, would increase NaCl reabsorption, leading to ECF volume expansion and hypertension, but it would also decrease, or in effect
"short-circuit," the lumen negative voltage that drives K+ secretion.
Genetic studies of different PHA2 pedigrees have shown linkage to chromosomes 1, 12, and 17. The gene involved on chromosome 1 has not yet been identified, but Wilson et al. (142) have recently shown that the genes associated with the other two encode members of a unique family of WNK ("with no lysine") serine-threonine kinases (146). A mutation in one intron of the WNK1 gene, which is located on chromosome 12, and various mutations in the coding regions of WNK4, on chromosome 17, lead to elevated levels of both kinases, i.e., a genetic gain of function (142). Wilson et al. (142) also showed that WNK4 is only expressed in the kidney, where it is localized to aldosterone-responsive segments of the nephron. WNK1 is expressed in several tissues, but in the kidney, it too is found only in the distal nephron. Finally, and most intriguingly, immunohistological studies showed that, whereas WNK1 is distributed throughout the cytoplasm of the distal nephron, WNK4 is present only in the junctional complexes where it was colocalized with ZO-1, a protein characteristic of these structures (142).
The above observations provide at least circumstantial evidence that
higher WNK4 activity is in some way associated with an increased
Cl permeability of the junctional complexes of the distal
convoluted tubule and/or CCD in at least one pedigree of PHA2 patients.
More important in the present context is the potential identification of a mechanism for Cl
reabsorption that could be just as
important as ENaC in regulating NaCl reabsorption by the distal
nephron. The activity of such a Cl
transporter would also
determine the strength of coupling between Na+ reabsorption
and K+ secretion. There are as yet no good candidates for
Cl
channels in the CCD or other regions of the
aldosterone-responsive segments of the nephron; however, since the
discovery that a specific protein (paracellin) mediates
Mg2+ and Ca2+ reabsorption through the
junctional complexes of the thick ascending limb (113),
the possibility of regulated Cl
movement through
junctional complexes no longer seems remote.
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OTHER HORMONAL REGULATORS OF SALT TRANSPORT IN THE CCD |
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The clear and consistent effects of ENaC subunit mutations and alterations in their regulation by abnormal mineralocorticoid metabolism have been seductive in advancing the optimistic view that a single gene defect might be the cause of essential hypertension. However, the connection between the rare genetic defects discussed above and essential hypertension is remote. In AME, glucocorticoid-remediable hypertension, and Liddle's syndrome, hypertension is usually severe and begins in childhood. Essential hypertension, on the other hand, typically begins later in life and progresses more slowly. It is only with certain forms (pedigrees) of PHA2 that a more slowly developing course is seen. This observation in no way discounts the importance of the single-gene defects described. Any one of them can cause severe hypertension, which clearly demonstrates the importance of transport regulation in the DCT and CCD. The question is only whether these particular candidate genes are likely to be involved in essential hypertension. Given the emerging picture of the polygenic nature of this and other diseases, it seems more likely that various coincidental combinations of gene alterations, diet, and environment are the cause.
The following sections discuss the possible role of VP, as well as autacoids and paracrine agents that alter the response to this hormone, in Na+ retention and hypertension. This focus on VP does not imply that it is potentially a more important or more likely contributor to derangements in ECF volume and blood pressure regulation but rather that the role of this regulatory system has been relatively neglected compared with others. Despite the fact that VP was the first hormone demonstrated to augment Na+ reabsorption in frog skin and toad bladder, the classic models of the CCD, it has traditionally been regarded to be a natriuretic hormone in mammals. Most of the studies that support this view, however, were conducted in water- or volume-loaded rats infused with VP (4, 137). More recent studies have demonstrated that VP can be antinatriuretic in euvolemic rats and humans (2, 4, 5, 22). VP was found to markedly decrease Na+ excretion even in isolated perfused kidney preparations, in which alternative explanations of the effect are obviated (73).
In the isolated, perfused rat CCD, VP acts synergistically with
aldosterone to stimulate both Na+ reabsorption and
K+ secretion. Both hormones individually increase
transport, but in combination the effect is greater than with either
hormone alone (20, 94, 95, 103, 105, 130, 131). VP also
stimulates 11-HSD2 activity in the rat CCD, and this mechanism has
been proposed to account for at least some of the synergism between VP
and aldosterone (1). The stimulation of Na+
reabsorption by VP is mediated by cAMP, which produces a rapid and
selective increase in the Na+ conductance of the luminal
membrane (104, 109), and the resulting depolarization of
the luminal membrane voltage increases K+ secretion
(103, 105). With Madin-Darby canine kidney cells as a
model of the rat CCD, we have used surface labeling to demonstrate that
cAMP increases the density of ENaC subunits in the apical membrane in
direct proportion to the increase in the amiloride-sensitive short-circuit current (80). Thus the acute action of VP
appears to be due primarily to trafficking of ENaC into that membrane.
Chronic treatment of rats with VP also leads to a dramatic increase in
the expression, primarily, of the - and
-ENaC subunits at both
mRNA (25) and protein (84) levels. It is
interesting to note that this effect is quite different from that
observed with aldosterone, which increases the expression only of
-ENaC and to a far lesser extent than the effect of VP on the
-
and
-ENaC subunits (77, 78, 84, 125).
The results in the rat CCD stand in marked contrast to earlier observations in the rabbit CCD. Although VP produced an initial hyperpolarization of the lumen negative voltage in the rabbit CCD that was suggestive of an increase in the luminal membrane Na+ conductance, after 15-30 min the voltage returned to control levels or below, and there was no stimulation of Na+ transport in the presence or absence of mineralocorticoid (20, 35, 57).
As summarized in Figs. 8 and
9, the rat and rabbit CCD also exhibit
quite different responses to other agents that appear to act as
autocrine or paracrine modulators of CCD transport. PGE2
has long been known to be an inhibitor of both Na+
reabsorption and the water permeability increase produced by VP in the
rabbit CCD (17, 19, 57, 124), possibly by elevation of
[Ca2+]i (53); however, neither
PGE2 nor elevation of [Ca2+]i has
any effect on Na+ transport or the water permeability
response to VP in the rat CCD (17, 19, 99). It seems
likely that, as proposed years ago by Holt and Lechene
(57), PGE2 produced by CCD cells in response
to VP acts as a negative-feedback inhibitor to prevent stimulation of
Na+ reabsorption and that this pathway is absent in the rat
CCD. PGE2 is now known to interact with two receptors,
EP1 and EP3, on the basolateral membrane of the
CCD (11). EP3 inhibits adenylyl cyclase via a
Gi protein, whereas EP1 activates the PLC
signaling system (11). The increase in
[Ca2+]i and protein kinase C (PKC) activity
that results from PLC stimulation has been shown to inhibit
VP-dependent Na+ transport and water permeability in the
rabbit, but not the rat, CCD (99).
|
|
In the rat CCD, catecholamines appear to be the primary modulators of
VP-dependent Na+ transport and water permeability, but they
are without effect in the rabbit CCD (17, 19). In the rat
CCD, dopamine inhibits VP action through a D4 receptor
(127, 128), and epinephrine or norepinephrine through an
2-receptor (51, 52, 141), both of which are
linked to Gi proteins associated with adenylyl cyclase, as
shown in Fig. 9. Dopamine, epinephrine, and clonidine have been
demonstrated to decrease VP-dependent cAMP production in the rat CCD
(17, 71).
This discussion of the differences between the response of the rat and
rabbit CCD to VP is not intended to be a thorough examination of the
regulatory processes involved but rather a prelude to the argument that
these differences may not just be "hardwired" in a given species
but may have physiologically relevant plasticity. In support of this
hypothesis, consider the following changes in the phenotype of the
rabbit CCD grown in culture. When rabbit CCD cells are grown in primary
culture, Na+ transport, measured as the amiloride-sensitive
short-circuit current, is indefinitely stimulated by VP
(15). This stimulation by VP is additive to the
stimulatory effect of overnight incubation with aldosterone, and it is
not inhibited by PGE2 or PKC as it is in the isolated
perfused rabbit CCD (15). In other words, rabbit CCD cells
grown in primary culture assume the regulatory phenotype of the rat CCD
with regard to the regulation of Na+ transport by VP. We
presently have only circumstantial evidence for the mechanism producing
this conversion. The atypical PKC -isoform is found in rabbit, but
not rat, CCD, and its expression disappears when rabbit CCD cells are
grown in culture, although other PKC isoforms are not downregulated
(140). However, regardless of the mechanism, the change in
the response of rabbit CCD cells to VP after growth in culture raises
the possibility that the human CCD might also acquire an enhanced
antinatriuretic response to VP in pathophysiological circumstances.
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IS THE ANTINATURETIC EFFECT OF VP INVOLVED IN HYPERTENSION OR EDEMATOUS STATES? |
---|
It is perhaps not surprising that the antinatriuretic effects of VP differ between rat and rabbit. Like the human, in antidiuresis the rabbit can only concentrate its urine to ~1,200 mosmol/l. In contrast, rat urine samples are in the range of ~1,000-3,000 mosmol/l and in antidiuresis exceed 3,000 mosmol/l. As pointed out by Bankir (4), omnivores such as rats and mice have a higher obligatory osmolal clearance due to higher urea production, normalized to body weight, than an herbivore such as the rabbit. Omnivores and carnivores thus require a higher urine osmolality to accommodate their higher rates of urea production and yet conserve water. The ability to concentrate the urine maximally is very dependent on water reabsorption in the cortical regions of the collecting duct, which is quantitatively much larger than the water reabsorption that occurs in the medullary collecting duct in antidiuresis (4, 61). Because the water permeability of the rat CCD is very high in the presence of VP, osmotic equilibration with the cortical interstitium occurs in the initial region. Distal to the point of equilibration, continued NaCl reabsorption in combination with the high water permeability leads to isosmotic fluid absorption. The rate of this isosmotic water reabsorption is directly proportional to the rate of NaCl reabsorption, and thus enhancement of Na+ reabsorption by VP in the rat CCD minimizes salt and water delivery to the medulla and maximizes water conservation (102).
In light of these observations, it is important to consider the possibility that VP may contribute to Na+ retention in humans. Of course, we do not know whether VP stimulates Na+ reabsorption in the human CCD under physiological conditions, but, given the similar concentrating ability of humans and rabbits, we might suspect not. Nevertheless, the necessary ingredients for such a response appear to be available in the rabbit CCD and are assembled during growth in culture. Can the response of human CCD to VP shift to cause Na+ as well as water retention, or can this antinatriuretic effect of VP be augmented if it already exists? If so, elevated VP might be an important contributor to Na+ retention and ECF volume expansion not only in hypertension but also in the edematous states produced by congestive heart failure, cirrhosis, and the nephrotic syndrome. There are no certain answers to these questions, but there is evidence linking VP to both hypertension and to the edematous states.
In the classic DOC-salt rat model, hypertension does not develop in the absence of plasma VP but can be restored by the selective V2-receptor agonist dDVP (6, 23, 72, 129, 150). Also, Yagil et al. (148) have shown that rats of the Sabra SBH/y strain, which provides a model of salt-sensitive hypertension, have elevated hypothalamic VP production and plasma VP levels on normal-salt intake compared with the corresponding control SBN/y line, which does not develop hypertension when placed on a high-salt diet. They concluded that elevated VP was a definite candidate gene for the salt-sensitive trait, at least in this model of hypertension (148, 149)
Clinical studies have also shown a correlation between plasma VP and hypertension. In healthy human subjects, Choukroun et al. (22) have shown that antidiuresis compromises the ability to excrete a Na+ load efficiently, which they attributed to the effect of VP on Na+ reabsorption by the CCD. These investigators further suggested that low water intake could compromise Na+ excretion even under conditions of normal daily intake. Bakris et al. (3) examined African-American and Caucasian patients with hypertension and found that baseline plasma VP was higher and the plasma renin lower in the former group. Furthermore, administration of a specific V2-receptor blocker significantly reduced blood pressure in the African-American, but not the Caucasian, group. In a large study that included both black and white patients, plasma levels of VP were positively correlated with arterial blood pressure and hypertension, particularly in those patients who also had low renin levels (151). Finally, in a recent study of sibling pairs of hypertensive (and hypercholesterolemic) black patients, Kotchen et al. (70) found that the response of plasma VP to NaCl loading was one of several heritable traits that were significantly associated with the hypertension.
There is also an association of VP with Na+ retentiveness in animal models of edematous states. For example, in rat models of chronic heart failure (147) and cirrhosis (39), it was found that specific V2-receptor antagonists induced diuresis and natriuresis. V2-receptor antagonists have also been suggested to be useful in treating both hypertension and Na+ and water retention in heart failure (12). Localization of these palliative effects to the V2 receptor indicates that they are a consequence of diminished antidiuretic and antinatriuretic effects of VP rather than vasodilation. Certainly, inhibition of the antidiuresis that causes the frequent development of hyponatremia in patients with congestive heart failure or cirrhosis is the most obvious and perhaps the most beneficial action of V2-receptor antagonists (13); however, they also relieve the extreme Na+ retentiveness that characterizes these disorders (9, 63).
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CONCLUSIONS |
---|
The genetic disorders discussed above provide ample evidence of
the importance of the aldosterone-responsive segments of the nephron
for regulating Na+ excretion. They also reveal highly
critical elements in this regulation, including the production and
metabolism of aldosterone and other adrenal steroids, the synthesis and
proper function of ENaC subunits, and possibly the Cl
permeability of the junctional complexes in the DCT and CCD.
These genetic defects and their pathophysiological consequences also provide more general support for the close association between the renal regulation of ECF volume and blood pressure proposed by Guyton (46, 47). One must be cautious, however, in applying these observations to any understanding of the pathophysiology of essential hypertension. Nevertheless, more subtle alterations in other processes that regulate Na+ reabsorption by the CCD, and perhaps other aldosterone-responsive nephron segments, may be components of essential hypertension, especially the low-renin, salt-sensitive variants. One candidate regulator is VP, which can, at least in some settings, act in synergy with aldosterone to increase Na+ reabsorption. This antinatriuretic action of VP, as well as its effect on the water permeability of the CCD, is variably inhibited in different animal models by activation of the PLC and PLA2 intracellular signaling systems, the autacoid actions of PGE2, and the paracrine actions of catecholamines, including dopamine. Therefore, alterations in any of these regulatory systems are also possible contributors to excessive Na+ retention or loss that lead to hypertension or salt wasting.
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ACKNOWLEDGEMENTS |
---|
I am grateful to the Renal Section of the American Physiological Society for the honor of my selection as the Gottschalk Distinguished Lecturer in 2001. I also express my admiration for the late Carl Gottschalk, a great renal physiologist and a great man who helped me and so many others in this field. I thank the reviewers of this article who called my attention to other studies and suggested other important points that I had overlooked in the original version. I also gratefully acknowledge my many collaborators who contributed to some of the studies discussed here and my support from National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-25519-21.
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FOOTNOTES |
---|
1 The Online Mendelial Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=OMIM) provides a superb source of additional information, including links to references, concerning the clinical presentation, biochemical etiology, and genetic defects involved in some of the diseases discussed in this reveiw. These resources are referenced by OMIM in parentheses together with the appropriate entry number, which in some cases is provided in place of references to the primary literature.
Address for reprint requests and other correspondence: J. A. Schafer, Depts. of Physiology and Biophysics and Medicine, Univ. of Alabama at Birmingham, Birmingham, AL 35294 (E-mail: jschafer{at}uab.edu).
10.1152/ajprenal.00068.2002
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