1 Laboratory of Molecular Medicine, Centre de Recherche de L'Université de Montreal, Campus Hotel-Dieu, Montreal, Quebec, Canada; 2 Laboratory of Biomembranes, Faculty of Biology, Moscow State University, Moscow, Russia; and 3 Department of Pharmacology and Toxicology, Wright State University, Dayton, Ohio
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ABSTRACT |
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Data obtained
during the last two decades show that spontaneously hypertensive rats,
an acceptable experimental model of primary human hypertension, possess
increased activity of both ubiquitous and renal cell-specific isoforms
of the
Na+/H+
exchanger (NHE) and
Na+-K+-2Cl
cotransporter. Abnormalities of these ion transporters have been found
in patients suffering from essential hypertension. Recent genetic
studies demonstrate that genes encoding the
- and
-subunits of
ENaC, a renal cell-specific isoform of the
Na+-K+-2Cl
cotransporter, and
3-,
1-, and
2-subunits of the
Na+-K+
pump are localized within quantitative trait loci (QTL) for elevated blood pressure as well as for enhanced heart-to-body weight ratio, proteinuria, phosphate excretion, and stroke latency. On the basis of
the homology of genome maps, several other genes encoding these transporters, as well as the
Na+/H+
exchanger and
Na+-K+-2Cl
cotransporter, can be predicted in QTL related to the pathogenesis of
hypertension. However, despite their location within QTL, analysis of
cDNA structure did not reveal any mutation in the coding region of the
above-listed transporters in primary hypertension, with the exception
of G276L substitution in the
1-Na+-K+
pump from Dahl salt-sensitive rats and a higher occurrence of T594M
mutation of
-ENaC in the black population with essential hypertension. These results suggest that, in contrast to Mendelian forms of hypertension, the altered activity of monovalent ion transporters in primary hypertension is caused by abnormalities of
systems involved in the regulation of their expression and/or function.
Further analysis of QTL in F2
hybrids of normotensive and hypertensive rats and in affected sibling
pairs will allow mapping of genes causing abnormalities of
these regulatory pathways.
ion transporters; genes; vascular and renal function
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INTRODUCTION |
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IN THE MID-1970's, it was reported
that the ouabain-insensitive component of monovalent ion exchange was
increased in aortic strips from spontaneously hypertensive rats (SHR)
(133) as well as in erythrocytes from SHR and patients with essential
hypertension (231, 232). Later on, these results were confirmed in
several laboratories and used as a basis to assess the involvement of abnormal membrane ion transport in the pathogenesis of primary hypertension (229, 230). During the last two decades, these abnormalities were shown to be caused by altered function of carriers implicated in monovalent ion transport, such as
Na+/H+
exchange,
Na+/Li+
(Na+/Na+)
countertransport,
Cl-dependent
Na+-K+
cotransport, and of the
Na+-K+
pump as well as Na+ and
K+ channels. The first part of
the present review summarizes our current knowledge on the activity of
these ion transport systems in primary hypertension. Recent progress
in molecular biology and the genetics of complex disorders led to
cloning of the above-listed ion transporters and identification of gene
loci for elevated blood pressure and its complications. These findings
enabled us to analyze the possible molecular and genetic
determinants of abnormal ion transport in primary hypertension and
their involvement in the pathogenesis of this disease.
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IDENTIFICATION OF ALTERED MONOVALENT ION TRANSPORTERS IN PRIMARY HYPERTENSION |
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Na+/H+ Exchange
Na+/H+ exchange provides electroneutral countertransport of Na+ (Li+) and H+ and is involved in the regulation of cell volume as well as intracellular concentrations of Na+ and H+. In epithelial cells, this ion carrier is also involved in transcellular movement of salt and osmotically obliged water. The cDNA encoding this carrier was first cloned from a human genomic DNA library, using the so-called H+ suicide strategy in a Na+/H+ exchange-deficient fibroblast line (252). mRNA probes showed that this form of transporter, referred to as housekeeping or ubiquitous Na+/H+ exchanger type 1 (NHE1), was expressed in all mammalian cells studied so far. Subsequently, the tissue-specific forms of the Na+/H+ exchanger (NHE2 to NHE6) derived from different genes were revealed by low-stringency screening of cDNA libraries with NHE1 cDNA or related oligonucleotide probes. Apart from differences in tissue expression, the cloned forms of the Na+/H+ exchanger possess different sensitivities to amiloride and its derivatives, as well as to the modulatory effect of 4
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The nucleotide sequence of NHE1 cDNA, possessing high homology in mammalian species (>90%), predicts a protein of ~91 kDa with a deduced secondary structure consisting of a short cytoplasmic NH2 terminus, 12 transmembrane domains, and an extended hydrophilic COOH terminus. All cloned forms of the Na+/H+ exchanger share these features of secondary structure of NHE1 with 60% homology in the sequence encoding a region from the 2nd to the 12th transmembrane domain and 30% homology in the COOH-terminal region. Complete removal of the NHE1 COOH terminus preserves allosteric activation of the exchanger by intracellular H+ with a Hill coefficient >2 but shifts pH dependence to a more acidic intracellular pH and completely abolishes the regulation of NHE1 by growth factors as well as by hormones and neurotransmitters coupled to seven membrane-domain-spanning receptors. The same results have been obtained for epithelial cell-specific forms of the Na+/H+ exchanger (for more details, see Refs. 162, 289, 296).
With the exception of a few cell types, the activity of the
Na+/H+
exchanger is quenched under basal conditions. Data on the functional properties of this carrier in primary hypertension have been mainly obtained from the study of
Na+-dependent amiloride-sensitive
H+ fluxes or amiloride-sensitive
Na+ uptake in
Na+-depleted cells with a prior
acidified cytoplasm (240, 264). With this approach, electrochemical
H+ gradient
(µH+)-induced
Na+/H+
exchange activity is increased in platelets, lymphocytes, neutrophils, erythrocytes, mesangial cells, kidney epithelial cells, freshly isolated segments of arteries, cultured vascular smooth muscle cells
(VSMC), and striated muscle cells from SHR as well as in erythrocytes,
platelets, lymphocytes, and immortalized lymphoblasts from patients with essential hypertension. In vivo studies using NMR
spectroscopy have revealed augmented activity of the
Na+/H+
exchanger in exercising skeletal muscle of SHR and essential hypertensive patients (Table 2). Table
3 shows that this difference is caused by
increased maximal activity of the
Na+/H+
exchanger rather than its sensitivity to intracellular
H+.
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In contrast to SHR, using the same experimental approach, we failed to detect any modification of this carrier's activity in erythrocytes and kidney epithelial cells from a colony of spontaneously hypertensive rats developed in Milan [Milan hypertensive strain (MHS); Table 2]. Based on a comparative analysis of abnormalities of this and other ion transporters (see below), it has been claimed that different strains of rodents with genetically determined hypertension can be employed for the study of different aspects of the pathogenesis of essential hypertension arising as a result of complex interactions of different genetic determinants and the environment (72). Indeed, in accordance with this mosaic theory of the pathogenesis of essential hypertension originally proposed by Page (211), an analysis of Na+/H+ exchange activity in erythrocytes from normotensive and hypertensive patients demonstrated that only 40-50% of subjects with essential hypertension possess increased Na+/H+ exchange activity similar to that seen in SHR, whereas, in the remaining essential hypertensive patients, this transporter is unaltered, as observed in MHS (27, 77).
Aside from primary hypertension, augmented Na+/H+ exchange activity has also been reported in blood cells, immortalized lymphoblasts, and skin fibroblasts from insulin-dependent diabetes mellitus (IDDM) patients with nephropathy (for recent review, see Ref. 286). It is well documented that hypertension and predisposition to it are essential components in the pathogenesis of IDDM. The mechanisms underlying this linkage are poorly understood. It is possible that enhanced Na+/H+ exchange activity is a common element in the pathogenesis of these diseases.
Based on the ubiquitous expression of NHE1 (Table 1), this isoform is assumed to be mainly involved in the heightened Na+/H+ exchange activity seen in blood cells and myocytes of SHR and patients with essential hypertension (Table 2). This conclusion is also supported by data on the lack of expression of epithelial cell-specific NHE2-NHE4 in SHR VSMC possessing enhanced Na+/H+ exchange activity (170). In the early 1990's, we reported data on increased Na+/H+ exchange activity in primary cultured renal epithelial cells from SHR (200). Simultaneously with our observation, an augmented rate of Na+/H+ exchange was demonstrated in isolated proximal tubules from SHR (43, 86). However, these studies did not evaluate the relative contribution of basolateral and renal cell-specific apical Na+/H+ exchanger in these abnormalities. Recently, using a novel, highly specific inhibitor of NHE1, HOE-694, it was shown that both NHE1 and NHE3 activities are increased in SHR proximal tubule cells (118, 140). Viewing these results in conjunction with data on the increased rate of amiloride-sensitive 22Na+ uptake in brush-border membrane vesicles from proximal tubules of MHS (218), it may be assumed that, in contrast to NHE1, both SHR and MHS exhibit enhanced NHE3 activity.
Can We Use Erythrocyte Na+/Li+ Countertransport as a Marker of NHE1 Activity?
In the mid-1970's, it was reported that the rate of Li+ efflux from human erythrocytes could be diminished by two- to threefold under isosmotic substitution of extracellular Na+ with Mg2+ and sucrose. Keeping in mind that Li+ substitutes for Na+ in most of the transport systems studied so far, the extracellular Na+-dependent component of Li+ efflux, termed Na+/Li+ exchange or countertransport, was assumed to represent a mode of operation of the equimolar Na+/Na+ exchanger (59, 216, 253). In 1980, we demonstrated that the rate of Na+/Li+ countertransport is increased in erythrocytes from patients with essential hypertension (29). During the last 15 years, this observation was reproduced in many laboratories (for review see Refs. 109, 114, 125, 230). Both enhanced maximal activity and apparent affinity to extracellular Na+ contribute to the enhanced rate of erythrocyte Na+/Li+ countertransport in essential hypertension (248, 257). For more details, see Ref. 114.Despite abundant (in >500 papers) data on augmented
Na+/Li+
countertransport in essential hypertension, the molecular mechanism of
this phenomenon is still unknown. The lack of a selective inhibitor of
this carrier complicates its purification by affinity chromatography and identification by an expression/cloning strategy. An attractive hypothesis suggests that enhanced erythrocyte
Na+/Li+
countertransport is a marker of increased activity of the housekeeping or renal cell-specific isoform of the
Na+/H+
exchanger (5, 125). However, detailed comparison of the properties of
erythrocyte
Na+/Li+
countertransport and
µH+induced
Na+ and
H+ fluxes in erythrocytes and in
cells transfected with the cloned isoform of the
Na+/H+
exchanger argues against this hypothesis. Thus it has been shown that
ATP depletion does not modify the activity of
Na+/Li+
countertransport in human erythrocytes but markedly inhibits erythrocyte
µH+-induced
Na+/H+
exchange as well as the activity of all cloned
Na+/H+
exchangers. One millimolar amiloride completely suppresses the activities of NHE1 and NHE2 and partly suppresses the activities of
NHE3 and NHE4 (Table 1) but does not affect erythrocyte
Na+/Li+
countertransport. Cell shrinkage and PMA, the activator of protein kinase C, are well-documented modulators of the activity of cloned forms of the
Na+/H+
exchanger (Table 1). However, these modulators do not affect the
activity of erythrocyte
Na+/Li+
countertransport. The most striking results were obtained by comparison of the relative activity of
Na+/Li+
countertransport and
µH+-induced
Na+/H+
exchange in erythrocytes of different species. Thus we failed to
demonstrate
Na+/Li+
countertransport in rat erythrocytes, whereas
µH+-induced Na+/H+
exchange in these cells was four- to fivefold higher compared with
human erythrocytes. In rabbit erythrocytes,
Na+/Li+
countertransport is 20-fold higher compared with human cells, whereas
the activity of
µH+-induced
Na+/H+
exchange in these species is about the same (for a more detailed comparison of the properties of erythrocyte
Na+/Li+
countertransport,
µH+-induced
Na+/H+
exchange, and cloned forms of the
Na+/H+
exchanger, see Ref. 193). These results show that erythrocyte Na+/Li+
countertransport cannot be used as a marker of enhanced NHE1 activity
in essential hypertension. Further experiments should clarify whether
these carriers are encoded by distinct genes or whether the special
properties of the erythrocyte
Na+/Li+
countertransporter are caused by posttranslational modification of
NHE1-NHE4 gene products during red blood cell maturation.
Cl-Dependent Cotransporters
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The first indication of altered activity of the ubiquitous form of the
Na+-K+-2Cl
cotransporter (NKCC1) in primary hypertension was obtained by Garay
with co-workers in a study of furosemide-sensitive ion transport in
erythrocytes from SHR and patients with essential hypertension (50,
81). These results, however, were obtained in cells treated with
sulfhydryl reagents and with inverse transmembrane
gradients of Na+ and
K+ that complicate their
implication for analysis of the activity of this carrier in vivo. Data
on the activity of this carrier in untreated cells are summarized in
Table 5. The outward mode of operation of
Na+-K+-2Cl
cotransport measured as the rate of furosemide/bumetanide-sensitive Na+ or
K+
(Rb+) efflux was reported to be
increased in erythrocytes from SHR and MHS by ~30 and ~50%,
respectively. The negative result obtained by Yokomatsu and co-workers
(302) was probably caused by overestimation of the rate of
22Na+
efflux at high internal Na+ in
erythrocytes from SHR. The importance of backflux correction to compare
the outward mode of operation of ion transporters has been discussed
previously in detail (228). In the case of
Na+-K+-2Cl
cotransport, this fact is especially important because of the inhibition of its activity by internal
Cl
and
Na+ (19, 101) and of the increased
sensitivity for intracellular Na+ in erythrocytes
from MHS (73). Both enhanced and unaltered Na+-K+-2Cl
cotransport activities have been reported in studies on the outward and
inward modes of operation of this carrier in erythrocytes from patients
with essential hypertension (Table 5). This discrepancy can be
explained by the presence of endogenous circulating inhibitors of
Na+-K+-2Cl
cotransport (272) that can affect the activity of the carrier in
freshly isolated blood cells. It should be noted that, in contrast to
the
Na+/H+
exchanger, which is enhanced in about one-half of the essential hypertensive population (see
Na+/H+
Exchange),
Na+-K+-2Cl
cotransport activity is increased in only 20-25% of essential hypertensive subjects possessing low plasma renin
activity (24, 41, 42).
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The data on
Na+-K+-2Cl
cotransport in nucleated cells from SHR are rather contradictory. Thus
the activity of this carrier has been reported to be increased,
decreased, or unaltered in VSMC from SHR (Table 5). For an analysis of
this discrepancy, it is important to underline that, in contrast to
mature mammalian erythrocytes, the permeability of nucleated cells for
Na+ is extremely high, and
Na+-K+-2Cl
cotransport activity may be altered due to the uncontrolled
modification of intracellular ion content caused by different ionic
composition of the medium and by treatment with ouabain.
Na+-K+-2Cl
cotransport seems to be also sensitive to the stage of cell cycle progression. Thus Raat and colleagues (237) reported that
Na+-K+-2Cl
cotransport is active in cells growing in culture but is quenched in
freshly isolated rat VSMC, endothelial cells, and rabbit proximal tubules. However, Yerby et al. (301) observed active
Na+-K+-2Cl
cotransport in freshly isolated endothelial cells. This point needs
further clarification.
According to data on the tissue distribution of
Na+-K+-2Cl
cotransport isoforms (Table 4), an enhanced rate of
bumetanide-sensitive ion flux in nonepithelial cells is caused by
hyperactivity of NKCC1. Data on
Na+-K+-2Cl
cotransport activity in epithelial cells are limited to a few publications. It has been shown that the diuretic response to furosemide is exaggerated in perfused kidney from MHS (249). The same
research team has reported that erythrocyte
Na+-K+-2Cl
cotransport activity in hypertensive patients is highly and positively correlated with Na+ loss caused by
furosemide administration (42, 238). Table 5 shows that
Na+-K+-2Cl
cotransport is increased in cultured tubular epithelial cells and in
membrane fractions from this nephron segment of MHS. However, the
relative contribution of basolateral NKCC1 and apical NKCC2 to this
abnormality is still unknown.
NCC activity in primary hypertension has not yet been explored. There
is no indication of modification of bumetanide-resistant K+ fluxes in erythrocytes from SHR
and patients with essential hypertension (202, 305) as well as in SHR
VSMC (151, 208), which suggests that
K+-Cl
cotransport activity is not altered in primary hypertension. In
contrast to K+, the rate of
ouabain-plus-bumetanide-insensitive
Na+ fluxes is slightly increased
in SHR erythrocytes (304). However, it is still not clear whether these
differences are caused by altered passive permeability of the plasma
membrane for this cation (membrane leakage) or caused by the presence
of a nonidentified ion carrier. The impact of increased surface area in
a fixed volume of packed cells due to diminished volume of erythrocytes
from SHR compared with normotensive Wistar-Kyoto rats (WKY) (225, 227)
should also be considered when these data are analyzed.
Amiloride-Sensitive Na+ Channels
Amiloride-sensitive Na+ channels provide selective movement of Na+ along its electrochemical gradient. These channels are more sensitive to amiloride than is NHE1 and are highly resistant to other potent inhibitors of the Na+/H+ exchanger, such as ethylisopropylamiloride (EIPA). Unlike neuronal TTX-sensitive Na+ channels, amiloride-sensitive channels do not show voltage-dependent gating. Channels possessing these properties are mainly expressed in the apical membrane of epithelial cells and are called epithelial Na+ channels (ENaC; for more details, see Refs. 83 and 215). Three homologous subunits of ENaC with Mr 72-79 kDa and classified asIn contrast to the monogenic forms of low-renin hypertension (see Search for mutations), data on the enhanced activity of ENaC in primary hypertension are limited to a few observations. In epithelial monolayers derived from the inner medullary collecting duct, cells from salt-sensitive Dahl rats (SS/JR) transport twice as much Na+ as cells from their salt-resistant counterparts (SR/JR) (126). On the basis of electrophysiological data, it was concluded that this difference may be caused by enhanced activity of the basolateral Na+-K+ pump or apical ENaC. Neither the maximal activity of the Na+-K+ pump nor its apparent affinity for intracellular Na+ and extracellular K+ was altered in salt-sensitive rats, suggesting higher Na+ transport via ENaC (127). Several types of nonepithelial cells including lymphoid cells also exhibit an amiloride-sensitive component of Na+ conductance (22). Bubien et al. (21) studied the electrophysiological properties of lymphocytes from 20 untreated patients possessing severe hypertension regardless of treatment with different classes of antihypertensive drugs. In this study, 14 patients were characterized by constitutively activated, amiloride-sensitive Na+ channels, whereas in other patients these channels appeared after elevation of intracellular cAMP content only. Interestingly, treatment with amiloride of patients possessing constitutively activated Na+ channels led to significant reduction of blood pressure (21). This finding should be further examined in more representative population studies and under comprehensive comparative analysis of the properties that amiloride-sensitive Na+ channels expressed in renal epithelium and in white blood cells.
Na+-K+ Pump
The Na+-K+ pump provides ouabain-sensitive hydrolysis of ATP coupled to the inward movement of K+ and outward movement of Na+, playing a key role in regulation of the intracellular concentration of monovalent cations. Because of its electrogenicity (3Na+/2K+), the Na+-K+ pump also contributes to the regulation of membrane potential in electrically excitable cells and other cell types with relatively high plasma membrane electrical resistance. The minimal functional unit of the Na+-K+ pump is composed ofIntensive studies of erythrocyte Na+/K+-ATPase activity in primary hypertension, performed in the late 1970's and early 1980's, did not reveal any systematic alteration of this ion transport pathway, measured as the rate of ouabain-sensitive ATP hydrolysis or by evaluation of the number of [3H]ouabain binding sites (for review, see Ref. 230). Several researchers reported a slight increment (by 15-25%) in the rate of ouabain-sensitive Na+ extrusion or K+ uptake in SHR erythrocytes (for review, see Ref. 304). Kuriyama and co-workers (151) demonstrated an enhanced rate of ouabain-sensitive 86Rb+ uptake in SHR VSMC. In contrast, this parameter was decreased by 15% in erythrocytes from MHS (12). These results, however, were obtained under uncontrolled concentrations of intracellular Na+, and thus a final conclusion cannot be reached without complete kinetic study. Special attention should also be paid to the partial reaction of Na+-K+-ATPase, i.e., ouabain-sensitive Na+/Na+ and K+/K+ exchange, since they might influence the real values of net ion fluxes mediated by this ion transport system (58).
Exciting results were obtained in studies of the
Na+-K+
pump in salt-sensitive hypertension. In 1993, Canessa and co-workers (28) reported that, in erythrocytes from salt-sensitive SS/JR rats, the
Na+/K+
coupling ratio of
1-Na+-K+-ATPase,
the sole erythrocyte isozyme, is close to 3:1 rather than 3:2, as
revealed in all types of cells investigated so far, including
erythrocytes from salt-resistant SR/JR rats. The same result was
obtained under analysis of net ouabain-sensitive
Na+ and
K+ fluxes and ouabain-sensitive
Na+/Na+
and
K+/K+
exchange, an additional mode of operation of this transporter in
salt-sensitive and salt-resistant rat strains developed in the Pavlov
Institute of Physiology, St. Petersburg, Russia (155). A difference in
ouabain-sensitive Na+ and
K+ fluxes between erythrocytes
from SS/JR and SR/JR rats was not detected by Zicha and Duhm (306).
However, in this study, the K+/Na+
ratio of ouabain-sensitive fluxes was close to 1:1, which was probably
caused by the presence of phosphate in the incubation medium. Indeed,
it is well documented that phosphate penetrates erythrocytes through
the anion exchanger and the augmented
K+/K+
exchange mode of the pump (58). Putative substrain differences in Dahl
rats from different colonies can also contribute to this discrepancy.
Mathematical simulation showed that functional manifestation of altered
modes of operation of the renal cell-specific
1/
1 Na+-K+
pump in proximal tubules
(3Na+:1K+)
is sufficient to explain the increased reabsorption of salt and
osmotically obliged water observed in salt-sensitive hypertension (210). Direct verification of this hypothesis is complicated due to
methodological problems in accurate measurement of the stoichiometry of
the
Na+-K+
pump in nonerythroid cells.
In contrast to conflicting results on the activity of the erythrocyte Na+-K+ pump in primary hypertension, two laboratories reported that the maximal activity (Vmax) of Na+-K+-ATPase is increased by 60-80% in membrane fractions from the MHS kidney cortex compared with the Milan normotensive strain (MNS) (176, 219). ATP-dependent, ouabain-sensitive Na+ uptake was also elevated in basolateral membrane inside-out vesicles from the kidney cortex of MHS. Because these differences were not linked to an increased number of ouabain-binding sites, they suggest altered properties of the pump itself or of its regulatory pathways (219). The possible mechanism of this abnormality is discussed in Systems Involved in Regulation of the Activity of Ion Transporters: Role of the Cytoskeleton Network.
Ca2+-Activated K+ Channels
In the mid-1980's, it was reported that outward K+ fluxes and membrane hyperpolarization induced by elevation of intracellular free Ca2+ concentration ([Ca2+]i) are augmented in erythrocytes from SHR (98, 202, 205) but not in MHS red blood cells (202). The level of Ca2+-induced hyperpolarization was also increased in erythrocytes from some patients with essential hypertension (202), suggesting an enhanced activity of Ca2+-activated K+ channels. Later on, heightened conductance of Ca2+-activated K+ channels was documented by studying Ca2+-induced ion currents in SHR VSMC with electrophysiological methods (6, 64, 246). Increased hyperpolarization was observed in platelets and VSMC from SHR by measurement of Ca2+-induced shifts in membrane potential using fluorescent dyes (P. V. Avdonin, personal communication), which also suggests hyperactivity of Ca2+-activated K+ channels.Three subclasses of Ca2+-activated
K+ channels have been defined in
nucleated cells based on their electrophysiological and pharmacological profiles as follows: 1)
small-conductance (10-20 pS) channels that are unaffected by
membrane potential and are sensitive to the bee venom toxin apamin,
2) intermediate-conductance channels (25-100 pS) that are also non-voltage gated but are insensitive to
the above-mentioned drug, and 3)
high-conductance (maxi-K or BK) channels (100-300 pS) that
are voltage dependent and inhibited by charybdotoxin (135). The
abnormalities of Ca2+-activated
K+ fluxes in VSMC are probably
caused by BK channels. This hypothesis was indirectly proved by
measuring resting artery strip contraction. In these experiments, it
was shown that application of charybdotoxin produces contraction in
artery strips from SHR but not from WKY (6). The relative contribution
of apamin- and charybdotoxin-sensitive K+ channels to enhanced
Ca2+-activated
K+ fluxes in erythrocytes and
platelets from SHR and patients with essential hypertension has not yet
been examined. It is important to mention here that voltage
insensitivity and low conductance (10-20 pS) impart unique
properties to erythrocyte charybdotoxin-sensitive channels (for more
details, see Ref. 195). Both the BK - and
-subunits involved in
charybdotoxin binding have been cloned from human and mouse cDNA
libraries (214). However, the genes encoding these proteins have not
been mapped.
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RELATIONSHIP BETWEEN ABNORMAL ION TRANSPORT AND HYPERTENSION |
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Data presented in IDENTIFICATION OF ALTERED MONOVALENT ION TRANSPORTERS IN PRIMARY HYPERTENSION show that NHE1 is increased in SHR and in one-half of the patients with essential hypertension. Erythrocytes from MHS, SHR, and ~25% of the patients with essential hypertension possess an increased activity of bumetanide-sensitive Na+ and K+ fluxes, thus indicating an enhanced activity of NKCC1. Data from several laboratories suggest that the enhanced activity of NHE3, NKCC2, Ca2+-activated K+ channels, and amiloride-sensitive Na+ channels, as well as an altered mode of operation of the Na+-K+ pump, can also contribute to altered monovalent ion transport across the plasma membrane in primary hypertension. In this section, we summarize data on the relationship between abnormalities of the above-listed ion transporters and hypertension.
Abnormal Ion Transport Is Not a Consequence of Chronic Hypertension
Similar to other membrane-bound proteins, the function of ion transporters is under the control of membrane lipid composition and viscosity. Indeed, evidence exists that the plasma level of triglycerides and cholesterol affects the activity of ion transporters in erythrocytes (33, 149, 276) and platelets (307). Long-term differences in salt diet can also modify the properties of ion transporters in these cells (46, 189). Hence, it may be assumed that the altered ion transport observed in primary hypertension is not due to an intrinsic cellular property but is caused by chronic exposure to a hypertensive milieu. In other words, the abnormalities may be considered a consequence of the disease rather than a genetically determined feature of primary hypertension. However, the evidence listed below argues against this assumption.First, in addition to freshly isolated blood cells, aortic strips, and proximal tubules, the enhanced activity of the Na+/H+ exchanger was revealed in cultured VSMC, renal epithelial cells from SHR, and immortalized lymphoblasts from patients with essential hypertension (Table 2). These cells were subjected to long-term incubation under conditions that rule out the extrinsic milieu as a causal factor of altered ion transport.
Second, in an elegant study by Bianchi and co-workers (12), (MHS × MNS) F1 hybrids were
subjected to X-ray irradiation and bone marrow transplantation from
parental donor strains.
Na+-K+-2Cl
cotransport in erythrocytes from
F1 MHS bone marrow recipients was
increased to the same extent as in donor strains compared with MNS bone
marrow recipients.
Third, numerous studies performed in different laboratories revealed no systematic alteration of ion transport in blood cells from patients with renal hypertension as well as in experimental rat models of secondary hypertension (see Refs. 109, 230, 305). Fortuno and co-workers (77) reported data on a partial correction of abnormalities of erythrocyte Na+/H+ exchanger under long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor quinapril. However, it is still unclear whether this effect was caused by blood pressure reduction or by direct interaction of the drug or its metabolites with cellular systems controlling the activity of the carrier. Indeed, using another ACE inhibitor, enalapril, Rosskopf and co-workers (242) found no modulation of the enhanced Na+/H+ exchanger in platelets from patients with essential hypertension.
Fourth, abnormal monovalent ion transport was demonstrated in young SHR and MHS before the development of hypertension (12, 43, 118, 231), as well as in young offspring of patients with essential hypertension (1, 270, 299).
Taken together, these data strongly suggest that abnormalities of ion transporters can be viewed as a genetically determined feature of primary hypertension rather than a consequence of long-term elevation of blood pressure.
Cosegregation of Ion Transport Abnormalities With Elevated Blood Pressure
The involvement of abnormal ion transport in the pathogenesis of primary hypertension was examined in the studies of Na+-K+-2ClFigure 1 shows that both (MHS × MNS)
F2 hybrids (12) and (SHR × WKY) F2 hybrids (144) possess a
statistically significant positive correlation between erythrocyte
Na+-K+-2Cl
cotransport activity, measured as outward bumetanide-sensitive Na+ efflux, and blood pressure,
with r = 0.520 and 0.509, respectively (P < 0.001). In addition, a study on
bumetanide-sensitive
86Rb+
influx in (SHR × WKY) F2
hybrids confirmed the positive correlation of the carrier's activity
with blood pressure (r = 0.301, P < 0.01) (225).
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We did not find a significant correlation between the rate of
erythrocyte
µH+-induced
Na+/H+
exchange and blood pressure in 35 F2 hybrids of SHR × WKY
(r = 0.196, P = 0.06) (196). However, two facts
should be taken into account when analyzing these results. First, the
mean values of
µH+-induced
Na+/H+
exchange in erythrocytes from (SHR × WKY)
F2 hybrids were two- and threefold
higher than in WKY and SHR progenitors, respectively. These results can
be explained as a consequence of complex gene-gene interactions.
Second, as mentioned in Can We Use Erythrocyte
Na+/Li+
Countertransport as a Marker of NHE1 Activity?, the
properties of erythrocyte
µH+-induced
Na+/H+
exchange and NHE1 in nucleated cells are significantly different, and
nucleated cells (listed in Table 2) rather than erythrocytes should be
used for the study of cosegregation of NHE1 activity and hypertension.
Genes Encoding Ion Transporters and Quantitative Trait Loci of Hypertension
Although the consideration of data obtained in quantitative trait loci (QTL) studies may appear discouraging because of the large number of potential hypertensive genes in different loci, it may help us to conclude whether or not genes encoding ion transporters or the most potent regulators of their activity are localized in loci that cosegregate with elevated blood pressure or with cardiac hypertrophy, hyperurecemia, albuminuria, stroke latency, and other phenotypes related to damage of target organs of hypertension, such as the heart, vessels, kidney, and brain.The search for QTL in essential hypertension meets with many
problems dealing with heterogeneity in the human population, shortage
of large and well-characterized pedigrees, as well as with variability
of environmental factors modifying the penetrance of disease.
Considering this, QTL analysis of
F2 and backcross hybrids derived
from inbred SHR and their normotensive counterparts has a substantial
advantage. Moreover, rat models constitute a unique tool to dissect the
genetic background of primary hypertension using
recombinant inbred and congenic strains. With these approaches, >30
chromosome loci were shown to be related to elevated blood pressure and
other intermediate phenotypes of hypertension. Table 6 indicates that the majority
of these loci exhibit strain specificity. The gender and age of animals
should also be considered when analyzing these data (36, 116). Despite
this diversity, three loci [1(b), 2(a), and 10(b)] possess
remarkable stability in all crosses studied so far (for more details
see Ref. 110).
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Recently, Bihoreau and colleagues (15) published a linkage map for all rat chromosomes. However, the density of the Rattus norvegicus genome map is still much reduced when compared with that of humans and mice. To broaden QTL analysis and enrich loci with candidate genes, we employed a comparative mapping technique. Using information on rat mapped genes collected from the "Rat Genome Database" in the Göteborg University server (http://ratmap.gen.gu.se), we retrieved data on chromosomal localization of the gene and on the human homologue. Then, using "Online Mendelian Inheritance in Man," the database created by Dr. V. A. McKusick (http://www3.ncbi.nlm.nih.gov/Omim), we proceeded to search for genes with positions close to the "anchor gene." This comparative genome mapping technique allows identification of homologous chromosomal regions in rats and humans. In most cases, construction of the synthenic map is impeded by evolutional chromosomal rearrangements that changed the gene order. For example, the order of QTL 1(b)-1(c)-1(d) in rats corresponds to at least five chromosomal segments in humans: (11p15)-(16q24-q13)-(3p)-(16p11-p13)-(19q13-q12). However, for some regions, homology was proved for the long piece of the chromosome. Thus locus 5(a)-5(b) corresponds to the human chromosomal region 1p34-pter, and QTL 10(a)-10(b) matches 17p13-17q24.
The comparative genome mapping approach is useful to establish a precise localization of the gene, even if it is not yet mapped. Thus chromosomal homology for rat chromosome 5 and human chromosomal piece 1p was reported by Szpirer and co-workers (280). QTL 5(a) and 5(b) were mapped around Anf and Et2 genes (Table 6). Using these genes as anchors and information on homologous human genes, we constructed a synthenic map for this region and were able to localize the NHE1 gene more precisely within locus 5(b) (Table 6). This region of chromosome 5 contains QTL for elevated blood pressure, stroke latency, and sensitivity to cerebral ischemic insult in F2 SHR × WKY and SHRSP × WKY (132, 243, 303). Data obtained for other regions with this analysis are briefly summarized below.
First, genes encoding the - and
-subunits of ENaC, the
3-,
1-, and
2-subunits of the
Na+-K+
pump, and NKCC2 are localized within QTL 1(b), 1(d), 3(c), and 10(a). These loci are involved in elevated blood pressure
as well as in enhanced heart-to-body weight ratio, proteinuria,
phosphate excretion, and stroke latency.
Second, several additional genes encoding monovalent ion transporters
can be predicted within QTL under synthenic analysis of human and rat
genome maps in accordance with the methodology described above: 1(b),
NCC and NHE5; 2(a), 2-subunits of the Na+-K+
pump; 4(d),
-ENaC; 5(b),
-ENaC and NHE1; 18(b), NKCC1.
Third, several lines of evidence suggest that, apart from monovalent ion transporters, hyperactive L-type Ca2+ channels and the plasma membrane Ca2+ pump contribute to intracellular Ca2+ overloading in primary hypertension (for recent review, see Ref. 194). Table 6 shows that QTL 1(b), 3(b), 4(d), 10(a), 13, and X contain mapped or provisionally positioned genes encoding different subunits of L-type Ca2+ channels (Cacn) and pump (Atp2).
Fourth, data presented in IDENTIFICATION OF ALTERED MONOVALENT ION TRANSPORTERS IN PRIMARY HYPERTENSION indicate an enhanced activity of renal cell-specific isoforms of the Na+/H+ exchanger (NHE3) and charybdotoxin-sensitive Ca2+-activated K+ channels (BK). QTL listed in Table 6 do not contain NHE3. Genes encoding BK subunits were not yet mapped.
An analysis of other genes inside QTL that could be related to the pathogenesis of hypertension was performed recently (110).
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POSSIBLE MECHANISMS INVOLVING ABNORMAL ION TRANSPORTERS IN THE PATHOGENESIS OF HYPERTENSION |
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Data presented in RELATIONSHIP BETWEEN ABNORMAL ION
TRANSPORT AND HYPERTENSION show that abnormalities of
ion transport pathways seen in several types of cells from SHR and
patients with essential hypertension are not caused by the hypertensive
milieu and may be involved in the pathogenesis of this disease as a
causal factor or as a factor of susceptibility for environmental stress
and the development of complications in target organs of
hypertension. Despite the widespread characteristics of ion transport
abnormalities, their manifestations in a limited number of cell types
point to their influence on the pathogenesis of the disease. Indeed,
complete substitution of bone marrow in (MHS × MNS)
F1 hybrids with bone marrow from
progenitors changed the ion transport properties of mature erythrocytes
toward those of donor strains but did not affect blood pressure (12),
demonstrating that altered ion transport in blood cells per se is not
involved in the pathogenesis of hypertension. This section deals with
the possible mechanism of ion transport abnormalities in the
pathogenesis of primary hypertension via their manifestation in the
kidney epithelium and vascular smooth muscle (Fig.
2). This approach is based on the
well-documented major role of kidney resetting and enhanced peripheral
vascular resistance in long-term maintenance of elevated blood pressure (99).
|
Ion Transport Abnormalities and Kidney Function
The key role of the kidney in long-term blood pressure elevation was originally proposed by Guyton et al. (100) and proven by transfer of blood pressure differences between MHS and MNS (13) as well as Dahl salt-sensitive and salt-resistant rats (44) after kidney transplantation. The same results were obtained in long-term studies on the effect of kidney transplantation from normotensive donors, with or without a family history of hypertension, on the development of hypertension in recipients (94). The pressure effect of transplantation seems to associate with the different activity of ion transporters, since the kidney from MHS and SHR caused accelerated Na+ reabsorption across the tubular epithelium (for more details see Ref. 72). A major role of kidney ion transporters in long-term blood pressure regulation was also supported by recent data on the identification of mutation sites in monogenic forms of hypertension and hypotension (see Search for mutations).Several lines of evidence presented in
Na+/H+Exchange,
Cl-Dependent
Cotransporters, and
Amiloride-Sensitive
Na+
Channels suggest that increased reabsorption of salt
and osmotically obliged water in low-renin hypertension can be caused
by enhanced activity of NHE3, ENaC, and NKCC2, which are mainly
localized in the brush-border membrane of the proximal tubule and thick ascending limb of Henle's loop. An altered mode of operation of the
1-Na+-K+
pump (see
Na+-K+
Pump) can also contribute to this phenomenon (Fig.
2). It was shown that transgenic mice overexpressing NHE1 exhibit
decreased urinary excretion and elevated systolic blood pressure after
excessive salt intake (153). Recent data on the antihypertensive effect of intracerebroventricular infusion of amiloride into rats with DOCA-salt hypertension (184) suggest that, besides renal
-ENaC,
-ENaC can also be involved in the development of
Na+-induced hypertension. However,
the mechanism by which basolateral NHE1 and nonepithelial
-ENaC
regulate kidney function is not currently well understood.
Ion Transport Abnormalities and Vascular Smooth Muscle Function
Vascular tone.
The hypothesis of the involvement of monovalent ion transporters in the
regulation of vascular tone was initially based on cross talk of the
Na+/H+
exchanger and
Na+/Ca2+
exchanger in the regulation of
[Ca2+]i
(17). In its initial form, this hypothesis was criticized due to the
lack of systematic indications of enhanced free intracellular Na+ concentration
([Na+]i)
in VSMC of hypertensive animals and relatively low activity of the VSMC
Na+/Ca2+
exchanger compared with other electrical excitable tissues (228, 230).
However, the hypothesis was revised recently after analysis of
intramembrane compartmentalization of the above-mentioned ion transporters. An immunohistochemical approach showed that the 3-subunits of the
Na+-K+
pump possessing the highest affinity for ouabain and for endogenous digitalis-like substances (DLS) (51, 112) as well as the
Na+/Ca2+
exchanger are colocalized in the same region of the VSMC sarcolemma overlying the endoplasmic reticulum, whereas the
1-subunits of the
Na+-K+
pump and the Ca2+ pump are
diffusely distributed along the sarcolemma. The compartment, abundant
in
3-Na+-K+
pump and
Na+/Ca2+
exchanger, was called plasmerosome (90, 134). On the basis of these
results, it was proposed that
[Na+]i
and
[Ca2+]i
in plasmerosomes differ from those in the bulk of the
cytoplasm, and abnormalities of intracellular
Ca2+ handling via enhanced
[Na+]i,
intracellular Na+/extracellular
Ca2+ exchange, and
Ca2+-induced
Ca2+ release from the endoplasmic
reticulum are limited only to the plasmerosome region (134). Enhanced
activity of Ca2+-activated
K+ channels (see
Ca2+-Activated
K+
Channels) can be viewed as a feedback mechanism that
partly protects VSMC from hypercontractility.
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MOLECULAR DETERMINANTS OF ABNORMAL ION TRANSPORT IN HYPERTENSION |
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Accelerated monovalent ion transport in primary hypertension can be caused by mutations of genes encoding ion transporters, leading to overexpression of gene products or to increased turnover number of ion carriers and open probability of ion channels. Functional abnormalities can also be triggered by the altered activity of systems involved in regulating the expression or activity of these transporters. In this section, we analyze the data concerning this topic.
Genes Encoding Ion Transporters
Search for mutations. NA+/H+ EXCHANGERS. As discussed in Na+/H+ Exchange, enhanced activity of NHE1 is one of the most potent hallmarks of altered ion transport in SHR and in patients with essential hypertension. By analysis of a single polymorphism located in the first intron of NHE1 and two polymorphisms in neighboring chromosome regions in Utah pedigrees, Lifton and co-workers (165) excluded NHE1 as a candidate gene involved in the augmented activity of Na+/Li+ countertransport as well as in essential hypertension selected by criteria of enhanced activity of this transporter. This conclusion is in line with cell physiology data on the different functional properties of NHE1 and erythrocyte Na+/Li+ countertransport (see Can We Use Erythrocyte Na+/Li+ Countertransport as a Marker of NHE1 Activity?). It should be stressed, however, that this population study did not rule out the presence of mutations in coding or untranslated regions of NHE1, which could be involved in the development of complica-tions of hypertension or even in the pathogenesis of this disease in patients with normal Na+/Li+ countertransport activity. The first hypothesis is supported by data on the presence of NHE1 within QTL of salt-induced increments of blood pressure and stroke latency (Table 6). To examine the presence of mutations in NHE1, we undertook single-stranded conformation polymorphism analysis of 23 fragments and partial sequencing of NHE1 cDNA from VSMC of stroke-prone SHR (SHRSP) possessing, similar to SHR, enhanced activity of the Na+/H+ exchanger (197). This analysis did not reveal any mutation in the coding region of NHE1 cDNA obtained by reverse transcription of mRNA from VSMC of SHR and SHRSP (188). As with NHE1, no mutation has been found in cDNA encoding kidney-specific NHE3 in SHR (118).
CL
|
Systems Involved in Regulation of the Activity of Ion Transporters: Role of the Cytoskeleton Network
The data summarized in Genes Encoding Ion Transporters show that evidence for mutations in genes encoding ion transporters in primary hypertension is limited to the observation of G276L substitution inIt should be stressed, however, that the candidate gene approach based
on our current knowledge of intracellular signaling mechanisms can be
misleading in the search for biochemical determinants of altered ion
transport in primary hypertension because of the presence of a set of
additional unidentified regulatory pathways. Thus, for example, Table 3
shows that altered NHE1 activity in primary hypertension is caused by
enhanced Vmax
rather than by altered affinity of the carrier for intracellular
H+. On the contrary, as is shown
in Fig.
3A,
hormones and neurotransmitters that raise
[Ca2+]i,
as well as growth factors and activators of protein kinase C (92, 185,
296), augment
Na+/H+
exchanger activity by increasing its sensitivity to intracellular H+, without affecting the maximal
activity of the carrier. Considering this, the
involvement of these regulators in the elevation of NHE1 in primary
hypertension should probably be ruled out. Unlike the above-mentioned
modulators of NHE1, cell volume (Fig.
3B), NaF, a nonspecific activator of
GTP-binding proteins (188), and the newly discovered
G13 and
G
12 (Fig.
3C) affect the
Vmax of the
Na+/H+
exchanger rather than its affinity for intracellular
H+. Intracellular signaling can
also be mediated by the
complex of activated GTP-binding
proteins (292). Furthermore, recently, Siffert and co-workers (265)
detected C825T polymorphism leading to deletion of 41 amino acids in
the
3-subunit of GTP-binding proteins. Genotype analysis of 853 subjects suggested a significant association of the mutated allele with
essential hypertension.
|
Side by side with the possible implication of GTP-binding proteins,
several observations listed below indicate that abnormalities of
cytoskeleton organization are involved in the altered activity of ion
transporters in primary hypertension. First, in VSMC (208) and in renal
epithelial cells (174, 175), modulation of
Na+-K+-2Cl
cotransport by activators of cAMP signaling was accompanied by cytoskeleton reorganization, and this was mimicked or blocked by
compounds affecting different components of the cytoskeleton network.
Second, in erythrocytes and renal epithelial cells, thermally induced
rearrangement of the cytoskeleton network is sufficient to induce a
drastic modulation of the basal activity of several ion transporters,
including the
Na+-K+-2Cl
cotransporter and
Na+/H+
exchanger, and to abolish their hormonal and volume-dependent regulation (78, 191). Third,
G
13-induced activation of NHE1 was accompanied by stress fiber formation in fibroblasts (123), suggesting that, like the volume-dependent regulation of ion
transporters (156, 192), this signaling pathway is also mediated by
cytoskeleton reorganization. Fourth, in contrast to other ion
transporters covered by this review, cellular mechanisms controlling
the activity of
Na+/Li+
countertransport are poorly understood (see Can We Use
Erythrocyte Na+/Li+
Countertransport as a Marker of NHE1 Activity?).
Recently, it was reported that the activity of this carrier may be
altered by two- to threefold under modification of a minor component of the erythrocyte cytoskeleton, a newly discovered 33-kDa protein (247).
Fifth, 100-fold dilution of cytoplasmic constituents during preparation
of resealed ghosts did not abolish the difference in activity of the
Na+-K+-2Cl
cotransporter between MHS and MNS erythrocytes (74), showing that NKCC1
activation in primary hypertension is not caused by cytoplasmic
components of signaling pathways. In contrast, disruption of the
erythrocyte cytoskeleton under preparation of inside-out vesicles
drastically affected the properties of furosemide/bumetanide-sensitive Na+ and
K+ fluxes (97) and completely
abolished the differences between MHS and MNS (73).
The first direct evidence of abnormal cytoskeleton organization in
primary hypertension was probably provided by the observation of an
altered profile of heat absorption by cytoskeleton proteins, revealed
by scanning microcalorimetry in intact and cytoskeleton-depleted erythrocyte membranes from SHR (95) and by electron paramagnetic resonance studies of membrane-bound protein mobility in erythrocytes from SHR (96). In erythrocytes, the cytoskeleton network is formed by
heterodimers of - and
-spectrin and actin bundles. This network
is assembled by means of a set of anchor proteins that includes adducin
(10, 171), a heterodimeric
/
protein that plays a major
role in the assembly of actin-based cytoskeleton through precise
regulation of actin filament length. Table 6 shows that genes encoding
adducin
,
, and
are located in chromosome fragments 1b, 4c,
and 14, which were identified as QTL for elevated blood pressure and
its complications. A few years ago, an immunochemical difference of
erythrocyte adducin between MHS and MNS led to the subsequent
identification of missense mutations in cDNA encoding
(F316Y),
(Q529R), and
(Q572K) adducin in MHS (14, 287). Furthermore,
-adducin polymorphism cosegregates with blood pressure in
F2 MHS × MNS hybrids (14).
There is no cosegregation of
- and
-adducin polymorphism per se
with blood pressure, but the MHS-like allele of these genes potentiates
the segregation of blood pressure with
-adducin polymorphism (14,
287). For our discussion, it is important to say that, besides
modulation of the cytoskeleton assembly, mutated adducin from MHS leads
to a 40% increase in
Na+-K+
pump Vmax in
transfected epithelial cells (288). The relationship of this mutation
to regulation of the activity of other ion transporters has not yet
been examined.
The presence of mutation in human -adducin leading to G460W
substitution was revealed in a population study of Caucasians from
Italy with a frequency distribution of GG, GW, and WW
alleles of 60, 37, and 3%, respectively. Furthermore, it was shown
that, in patients with GW and WW alleles, the probability of
salt-induced hypertension was eightfold higher than in patients with
the WW allele (40). These data constitute the first example of the association of polymorphism occurring in the same gene with
hypertension in rats and humans. It should be mentioned, however, that,
in contrast to hypertensive subjects from Italy, no association between hypertension and
-adducin G460W polymorphism was established in
studies of hypertensive and normotensive subjects from Japan (139) and
Scotland (136). These observations and data on the T594M
-ENaC
mutation limited to black hypertensive subjects from London (see
Search for mutations) as well as the
inconstancy between populations for a number of other proposed genes,
such as ACE, angiotensinogen, and the Sa gene, underlie
the complex race- and population-dependent interplay of gene-gene and
gene-environment interactions in the maintenance of elevated blood
pressure in essential hypertension (110, 115).
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CONCLUSION AND PERSPECTIVES |
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The data summarized in IDENTIFICATION OF ALTERED
MONOVALENT ION TRANSPORTERS IN PRIMARY HYPERTENSION
show that enhanced activity of the
Na+/H+
exchanger,
Na+-K+-2Cl
cotransporter, epithelial Na+
channels, and Ca2+-activated
K+ channels and the altered mode
of operation of the
Na+-K+
pump contribute to altered membrane permeability of monovalent ions in
primary hypertension. Several lines of evidence presented in
RELATIONSHIP BETWEEN ABNORMAL ION TRANSPORT AND
HYPERTENSION and POSSIBLE MECHANISMS
INVOLVING ABNORMAL ION TRANSPORTERS IN THE PATHOGENESIS OF
HYPERTENSION suggest that abnormalities of these ion
transporters can be involved in the pathogenesis of this disease.
However, the mechanisms of these alterations remain unclear. Indeed,
despite identification of the genes encoding some of these ion
transporters within QTL related to the pathogenesis of hypertension,
analysis of cDNA structure did not reveal any mutation in the coding
region of genes encoding the ubiquitous and renal cell-specific
isoforms of the
Na+/H+
exchanger as well as of genes encoding subunits of epithelial Na+ channels, with the exception
of the T594M mutation of
-ENaC in a limited population of blacks
with essential hypertension. The involvement of single point mutations
of the
Na+-K+
pump
1-subunit and the altered operational mode of this transporter in Dahl salt-sensitive rats have not yet been examined. Viewed collectively, these results suggest that, in contrast to Mendelian forms of symptomatic hypertension, the enhanced activity of ion transporters in primary hypertension is mainly caused by abnormalities of systems involved in the regulation of their expression and/or functioning. Keeping in mind the diversity of gene products involved in
the regulation of expression and function of ion transporters, we
believe that the mapping of ion transport phenotypes in
F2 hybrids and recombinant inbred
strains obtained by a cross of hypertensive and normotensive
progenitors as well as human genetic studies, such as mapping of QTL
for altered ion transporters in affected sibling pairs,
will lead to the identification of genetic mechanisms underlying these
abnormalities. This positional cloning approach as well as genetic
loss-of-function and gain-of-function experiments is required in
studies with transgenic animals to analyze the involvement of abnormal
ion transporters in the long-term maintenance of elevated blood
pressure and in the complications of chronic hypertension. Besides this
issue, identification of the genetic basis of ion transport
abnormalities may lead to the development of individual therapies for
this disease based on pharmacogenetic approaches. Thus, for example, it
was shown that polymorphism in QTL 2(a) lacking genes encoding any
subunits of L-type Ca2+ channels
(Table 6) influences the blood pressure response to Ca2+ channel blockers (294),
whereas patients bearing the G460M mutation in
-adducin benefit from
treatment with diuretics (40).
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ACKNOWLEDGEMENTS |
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We acknowledge the late Mitzy Canessa for her highly significant contribution to these studies.
![]() |
FOOTNOTES |
---|
The secretarial help of Monique Poirie and Josee Bedard-Baker and editorial assistance of Ovid Da Silva are greatly appreciated.
This work was supported by grants from the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada, Pfizer Canada, Bayer Canada, and the National Institutes of Health of the United States (SCOR Program).
S. N. Orlov was a fellow of the International Society of Hypertension (Pfizer Award) and a scholar of Servier Canada. V. A. Adarichev was the recipient of a fellowship from the Medical Research Council of Canada.
Present address of V. A. Adarichev: Dept. of Pharmacology, Univ. of Illinois at Chicago, 835 South Wolcott Ave., Chicago, IL 60612.
Address for reprint requests: S. N. Orlov, Centre de Recherche, Centre Hospitalier Universitaire Montreal, 3850 rue St-Urbain, Montreal, PQ, Canada H2W 1T8 (E-mail: orlovs{at}ere.umontreal.ca).
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