Download Role of the distal convoluted tubule in renal Mg handling: molecular

Magnesium Research 2011; 24 (3): S101-8 EUROPEAN MAGNESIUM MEETING - EUROMAG BOLOGNA 2011
doi:10.1684/mrh.2011.0289
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 07/05/2017.
Role of the distal convoluted tubule
in renal Mg2+ handling:
molecular lessons from inherited
hypomagnesemia
Silvia Ferrè, Joost J.G. Hoenderop, René J.M. Bindels
Department of Physiology, Radboud University Nijmegen Medical Centre, The Netherlands
Correspondence: R.J.M. Bindels, Department of Physiology (286), Radboud University Nijmegen Medical Centre,
PO Box 9101, 6500 HB Nijmegen, The Netherlands
<[email protected]>
Abstract. In healthy individuals, Mg2+ homeostasis is tightly regulated by the
concerted action of intestinal absorption, exchange with bone, and renal excretion. The kidney, more precisely the distal convoluted tubule (DCT), is the final
determinant of plasma Mg2+ concentrations. Positional cloning strategies in
families with hereditary hypomagnesemia identified defects in several proteins
localized in the DCT as causative factors. So far, the identified actors involved
in Mg2+ handling in the DCT include: the transient receptor potential channel
melastatin member 6, the pro-epidermal growth factor, the thiazide-sensitive
Na+ -Cl- cotransporter, the ␥-subunit of the Na+ /K+ -ATPase, the hepatocyte
nuclear factor 1B, the potassium channels Kv1.1 and Kir4.1, and the cyclin
M2. In the years to come, the identification of new magnesiotropic genes and
related proteins will further clarify the role of the kidney in Mg2+ homeostasis,
and will potentially lead to new therapeutic approaches for hypomagnesemia.
Key words: familial hypomagnesemia, distal convoluted tubule, transcellular
transport
In the human body, Mg2+ homeostasis relies on
tissues transporting and/or storing Mg2+ (mainly
kidney, intestine and bone), hormones that modulate its mobilization [1], and sensors controlling
the release of magnesotropic hormones and regulation of the transport of Mg2+ in tissues [2, 3]. The
dynamic actions of these homeostatic elements
guarantee the maintenance of normal plasma
Mg2+ concentrations within a narrow range (0.71.1 mmol/L). In particular, the kidney is the final
determinant of circulating Mg2+ levels. Under
physiological conditions, the kidney filters 80%
of the total plasma Mg2+ , but the tight regulation of the reabsorption processes that take
Presented in part at the European Magnesium
Meeting - EUROMAG Bologna 2011, San Giovanni in
Monte, Bologna, Italy, June 8-10, 2011.
place along the nephron guarantee less than 5%
Mg2+ waste in the urine. In short, 10 to 20%
of the filtered Mg2+ is reabsorbed by the proximal tubule (PT), whereas the majority (65-70%)
is reabsorbed in the cortical thick ascending limb
(TAL) of Henle’s loop. Here, the positive transepithelial voltage drives Mg2+ across a paracellular
pathway that involves the tight junction proteins,
claudin-16 and claudin-19 [4, 5]. Defects in either
protein are causative for familial hypomagnesemia with hypercalciuria and nephrocalcinosis
(FHHNC; OMIM 248250); transgenic mice lacking
either claudin-16 or claudin-19 reproduce many
of the features of FHHNC [5]. Of the filtered
Mg2+ , 10-15% reaches the distal convoluted tubule
(DCT), where 70 to 80% is reabsorbed. In the
DCT, the transepithelial voltage is negative and
Mg2+ reabsorption occurs in an active transcellular manner. As the more distal nephron segments
S101
To cite this article: Ferrè S, Hoenderop JJG, Bindels RJM. Role of the distal convoluted tubule in renal Mg2+ handling: molecular
lessons from inherited hypomagnesemia. Magnes Res 2011; 24(3): S101-8 doi:10.1684/mrh.2011.0289
S. FERRÈ ET AL.
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are largely impermeable to Mg2+ , the DCT plays
an important role in determining the final urinary
excretion [6].
The DCT consists of two subsegments named
DCT1 and DTC2, with DCT1 being primarily
involved in overall Mg2+ handling. In the DCT1,
Mg2+ transport from the pro-urine into the cell
is mediated by the apical transient receptor
potential melastatin subtype 6 (TRPM6), and is
critically influenced by ATP-dependent Na+ reabsorption [7, 8] and cellular energy metabolism [9].
So far, the basolateral mechanism responsible for
Mg2+ transport from the intracellular compartment towards the blood remains unknown.
Hypermagnesemia (serum Mg2+ >1.1 mmol/L)
is a rare condition and mainly occurs in cases
of renal insufficiency. Dialysis represents the
most rapid therapeutic intervention to lower
Mg2+ levels. On the other hand, hypomagnesemia
(serum Mg2+ <0.70 mmol/L) is a common electrolyte disturbance observed in up to 12% of
hospitalized patients and 65% of patients in the
Intensive Care Unit. The clinical manifestations
in patients with hypomagnesemia include neuromuscular irritability, such as tetany and seizures,
cardiac arrhythmias, secondary hypocalcemia and
secondary hypokalemia. Patients suffering from
severe hypomagnesemia are often supplemented
with Mg2+ . Acute intravenous infusion is usually
reserved for patients with symptomatic hypomagnesemia, whereas in asymptomatic hypomagnesemic patients, oral replacement represents the
preferred route of administration, even if limited
by the amount of Mg2+ that causes diarrhea.
Hypomagnesemia can be primary to homeostatic defects, i.e. either intestinal or renal losses.
Measurement of urinary Mg2+ excretion before
Mg2+ replacement helps to determine whether
the hypomagnesmic state results from renal or
extra-renal causes. Moreover, hypomagnesemia
can be secondary to treatment with therapeutic
agents [10-12] or to other medical conditions [13].
In recent years, several, rare, inherited forms
of hypomagnesemia have been described in the
literature [14]. Inherited hypomagnesemia
manifests mostly during infancy when serum
Mg2+ levels can vary from slightly below the physiological concentration to up to <0.20 mmol/L.
Genome-wide linkage analysis for affected family
members have allowed the identification of new
genes and derived proteins involved in renal Mg2+
handling (figure 1).
This review aims to summarize genetic and
functional findings that elucidated the pathophysiology underlying inherited forms of hypomagnesemia that affect Mg2+ transport in the DCT.
DCT
ϒ subunit of
Na,K-ATPase
?
NCC
CIHNF1B
Na+
Na+
Kv1.1
K+
Transcripition
Kir4.1
Mg2+
CNNM2
TRPM6
Apical
Basolateral
EGF
Figure 1. Schematic representation of the molecular players in which defects cause dysfunctional
Mg2+ handling in the distal convoluted tubule (DCT).
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Molecular lessons from inherited hypomagnesemia
Monogenic defects disrupting Mg2+
reabsorption in the DCT
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Transient receptor potential channel
melastatin member 6
Two independent research groups identified the
transient receptor potential channel melastatin
member 6 (TRPM6) as the causative gene in
the autosomal recessive disorder called hypomagnesemia with secondary hypocalcemia (HSH,
OMIM 602014) [15, 16]. HSH patients develop
severe hypomagnesemia (0.1-0.4 mmol/L), secondary hypocalcemia, disturbed neuromuscular
excitability, muscle spasms, tetany and convulsions. Using immunohistochemistry, the TRPM6
protein was shown to localize at the apical membrane of the DCT1 and at the brush-border
membrane of the intestine [17]. Indeed, the
homozygous and compound heterozygous mutations identified in HSH patients lead to both
impaired intestinal Mg2+ absorption and renal
re-absorption [15, 16]. TRPM6, and its closest
homologue TRPM7, are unique epithelial Mg2+
channels that couple ion transport to a ␣-kinase
activity. In recent years, intense research has
focused on the regulatory factors of the TRPM6
␣-kinase domain [18]. Overall, TRPM6 can be
defined as the gatekeeper of Mg2+ homeostasis,
and many proteins that are found mutated in
inherited forms of hypomagnesemia directly affect
TRPM6 or alter the driving force for Mg2+ influx
via the channel.
Epidermal growth factor
Using a whole-genome linkage analysis, mutation c.3209C>T (p.Pro1070Leu) in the EGF
gene was shown to be the causative defect in
recessive isolated renal hypomagnesemia (IRH,
OMIM 611718) [19]. IRH was originally described
by Geven et al. in two siblings who presented
epileptic seizures, moderate mental retardation,
hypomagnesemia (0.53-0.66mmol/L) and normal
Ca2+ handling [20]. The EGF gene encodes for
pro-EGF, a small peptide hormone expressed in
several organs, including gastrointestinal tract,
respiratory tract, and kidney (primarily DCT).
Here, after insertion at the basolateral membrane,
pro-EGF is processed into soluble EGF that is able
to stimulate locally the EGF receptor (figure 1).
EGF was defined as the first magnesiotropic
hormone when patch clamp analysis revealed
that EGF significantly stimulated the activity
of TRPM6. Later, biochemical experiments
reported that EGF increases TRPM6 cell surface
abundance by redistributing the channel from
intracellular vesicles to the plasma membrane
via signaling through Src kinases and Rac1
[21]. The mutation observed in the family with
IRH, disrupts the basolateral-sorting motif in
pro-EGF. Thus, mutated pro-EGF is impaired in
its routing towards the basolateral membrane,
leading to disturbed stimulation of the EGFR and
subsequent reduced Mg2+ transport by TRPM6.
NaCl cotransporter
Gitelman syndrome (GS, OMIM 263800) is an
autosomal recessive disorder characterized by
hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria and commonly observed
periods of muscle weakness and tetany. The underlying causes for GS are homozygous or compound
heterozygous mutations or deletions in the
SLC12A3 gene encoding for the thiazide-sensitive
NaCl cotransporter (NCC) [7]. NCC is expressed
at the apical membrane of the DCT1, where it
facilitates reabsorption of Na+ and Cl- from the
pro-urine into the cell (figure 1). Inactivating
mutations in NCC, by chronic thiazide administration, causes renal NaCl wasting. This in turn
leads to extracellular volume contraction with
subsequent activation of the renin-angiotensinaldosterone system, increased Na+ reabsorption
in the more distal segments of the nephron in
exchange for K+ , and thereby development of
hypokalemic alkalosis. The disturbances in mineral metabolism observed in the course of GS are
secondary to the defects in NCC. The observed
hypocalciuria is caused by an increased proximal tubular reabsorption in response to the mild
volume depletion. The exact mechanism at the
basis of the hypomagnesemia remains to be determined, but is likely due to a reduced abundance of
TRPM6, leading to renal Mg2+ wasting. It has been
suggested that increased aldosterone levels may
be the reason for the decreased TRPM6 expression
[22].
␥-Subunit of the Na+ /K+ -ATPase
Isolated dominant hypomagnesemia with hypocalciuria (IDH, OMIM 154020) is caused by a
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S. FERRÈ ET AL.
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c.121G>A (p.Gly41Arg) mutation in the FXYD2
gene, encoding for the ␥-subunit of the Na+ /K+ ATPase [23]. Patients with IDH also suffered from
convulsions, probably due to the low serum Mg2+
levels (<0.4mmol/L). The ␥-subunit (FXYD2) is a
type I transmembrane protein that modulates the
kinetics of the Na+ /K+ -ATPase by altering its affinity for K+ and Na+ at the basolateral membrane of
kidney tubules [24]. The Na+ /K+ -ATPase, in turn,
guarantees a local negative membrane potential
that drives the trans-epithelial salt reabsorption. Upon oligomerization, the mutated ␥-subunit
impairs routing of the wild type protein towards
the plasma membrane, in accordance with the
dominant inheritance of the disease [25]. Of note,
the FXYD2 gene can be alternatively transcribed
into two main variants, namely ␥a and ␥b, that
differ only at their extracellular N-termini [26].
Immunostaining of ␥b has been found specifically
in DCT1, whereas ␥a is more broadly expressed
along the nephron [27]. The p.Gly41Arg mutation
localizes in the unique transmembrane domain
of the protein and therefore, affects both isoforms. However, the exact molecular mechanism
by which the ␥-subunit ultimately modulates
Mg2+ handling in DCT remains to be established. Speculatively, mutation of the ␥-subunit
causes a reduction in the activity of the Na+ /K+ ATPase that induces depolarization of the apical
membrane and decreases the Mg2+ transport via
TRPM6. Alternatively, the ␥-subunit may work as
an accessory protein of other Mg2+ -related protein
complexes.
Hepatocyte nuclear factor 1 homeobox B
Hetererozygous mutations in the HNF1B gene
are responsible for a dominant renal cysts and
diabetes syndrome (RCAD, OMIM 137920) that
includes both renal and extrarenal manifestations. HNF1B encodes for the transcription factor
hepatocyte nuclear factor 1 homeobox B that is
critically involved in early vertebrate development and tissue-specific transcription in kidney,
liver, pancreas and genital tracts [28, 29]. Defects
in the HNF1B gene include whole-gene deletion
in about 50% of the patients, whereas point mutations are detected in most of the remaining cases,
along the entire coding sequence. In a large cohort
of patients, no correlation was found between the
type of mutation and the type and/or severity
of renal disease [30]. Renal Mg2+ wasting with
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hypocalciuria occurs in up to 50% of the cases.
Moreover, HNF1B nephropathy in adulthood is
accompanied by hypokalemia in nearly half of the
cases [31]. So far, screening for HNF1B binding
sites in genes known to affect renal Mg2+ transport
has revealed a role for HNF1B in the transcriptional regulation of the FXYD2 gene [32], and
in particular of the promoter leading to the ␥asubunit protein [27]. Nevertheless, the molecular
mechanisms responsible for the hypomagnesemic
phenotype remain unknown. In the future, a comprehensive study of serum Mg2+ values in HNF1B
families, and a genotype-phenotype correlation
between the genetic defects and electrolyte levels,
will help to elucidate the molecular basis of Mg2+
wasting in the DCT.
Kv1.1
A positional cloning approach in a family with isolated autosomal dominant hypomagnesemia lead
to the identification of a c.763A>G (p.Asn255Asp)
mutation in the KCNA1 gene, encoding the
voltage-gated potassium (K+ ) channels Kv1.1
[33]. The affected family members present with
recurrent muscle cramps, tetany, tremor, muscle weakness, cerebellar atrophy, and myokymia,
in addition to low serum Mg2+ levels (0.280.37 mmol/L). When overexpressed in human
embryonic kidney cells, Kv1.1 hyperpolarizes
the plasma membrane compared to mock DNA
transfected cells. The conserved asparagine at
position 255 localizes in the third transmembrane segment of Kv1.1 and was found to be
necessary for the voltage dependence and kinetics of channel gating [34]. Substitution of the
asparagine for aspartic acid leads to a nonfunctional channel, with a dominant negative
effect on the wild type Kv1.1 [33]. Localization
of Kv1.1 in DCT1 suggests that Kv1.1 might
establish a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+
reabsorption.
Previously identified mutations in Kv1.1 are
characterized by episodic ataxia (EA1, OMIM
160120) [35, 36], but show no hypomagnesemia.
On the other hand, family members with the
p.Asn255Asp mutation showed slight atrophia of
the cerebral vermis and myokymic discharge.[33]
Further studies should elucidate how distinct
mutations in Kv1.1 can result in the tissue-specific
phenotypes.
Molecular lessons from inherited hypomagnesemia
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Kir4.1
Mutations in the KCNJ10 gene, encoding an
inwardly rectifying K+ channel (Kir4.1), were
identified as causative defects for a new syndrome
of hypomagnesemia. Affected patients suffered
from seizures, sensorineural deafness, ataxia,
mental retardation, and electrolyte imbalance
(SeSAME) [37]/epilepsy, ataxia, sensorineural
deafness, and renal tubulopathy (EAST) [38]
syndrome (OMIM 612780). The renal phenotype associated with loss of KCNJ10 function
comprises a state of Gitelman-like salt wasting,
with hypokalemic metabolic alkalosis, hypomagnesemia and hypocalcemia. Positive Kir4.1
immunostaining was found at the basolateral
membrane of the DCT. Here, Kir4.1 allows K+
recycling to enable normal activity of the Na+ /K+ ATPase (figure 1). The Na+ /K+ -ATPase generates
a negative membrane potential and provides a
Na+ gradient for NCC to facilitate transport of
Na+ from the lumen into the cytoplasm. Impairment of the electrogenic Na+ /K+ -ATPase activity
at the basolateral membrane due to Kir4.1 loss
of function, may result in depolarization of the
apical membrane and therefore reduction of the
Mg2+ influx via TRPM6. It was recently shown
that CaSR interacts with and inactivates Kir4.1
[39]. Evidence for this interaction suggests that
hypomagnesemia occurring in patients with activating mutations in CaSR [40] might affect
renal Na+ transport, and therefore causes Mg2+
wasting, via the same mechanisms as loss of
function mutations in Kir4.1. Kir4.1 is often
found as a heteromeric complex with Kir5.1.
Interestingly, in Kir5.1 knock-out mice (Kir5.1-/- ),
homomeric Kir4.1 channels are pHi -insensitive
and constitutively highly active. This increases
the basolateral K+ conductance in the DCT leading
to the development of a mirror-image phenotype to
SeSAME/EAST syndrome [41].
CNNM2
Among the numerous proteins associated with
Mg2+ transport in eukaryotes [42], cyclin M2
(CNNM2) certainly plays a role in Mg2+ homeostasis. Early findings suggested the involvement
of CNNM2 in Mg2+ handling, based on a microarray and a genome-wide association study
[43, 44]. Using a candidate screening approach
in two unrelated families with unexplained
dominant hypomagnesemia (serum Mg2+ 0.51-
0.36 mmol/L, OMIM 613882), Stuiver et al.
identified two mutations in the CNNM2 gene:
the heterozygous deletion c.117delG and the heterozygous missense mutation c.1703C>T [45].
The deletion c.117delG (p.Ile40SerfsX15) leads to
a truncated protein with uncharacterized function, whereas the missense mutation c.1703C>T
(p.Thr568Ile) causes a substitution in one of
the two highly conserved cystathionine betasynthase (CBS) domains, known to be important
for dimerization of several transporters as well
as for Mg2+ -dependent gating of bacterial MgtE
channel [46]. Patch clamp experiments with
wild type CNNM2 in human embryonic kidney
cells revealed a Mg2+ -sensitive Na+ current that
was clearly diminished in p.Thr568Ile mutant
CNNM2 transfected cells [45]. Three splice variants of CNNM2 have been identified in mammals.
The p.Thr568Ile substitution affects the coding
sequence of variant 1 and 2 of CNNM2 [47].
Although only variant 1 seems to be involved in
Mg2+ transport [47], in the future, the physiological relevance of the two isoforms and their
effect on the wild type protein should be investigated. Interestingly, CNNM2 shows a clear,
basolateral localization, both in the thick ascending limb of Henle’s loop and the DCT of the kidney,
appointing CNNM2 as a putative candidate for
an Mg2+ extrusion mechanism. Nevertheless, the
wide expression pattern of CNNM2 being present
in many tissues, and no evidence of a CNNM2mediated Mg2+ current in mammalian cells point
more likely to a Mg2+ -sensing function of the protein rather than its direct role in transcellular
Mg2+ transport in the DCT [45].
Conclusion
In summary, genetic studies in cases of familial
hypomagnesemia revealed defects in several proteins, with a predominant expression in the DCT1
of the kidney (figure 1). Elucidation of the molecular origin underlying these defects has greatly
increased our understanding of renal Mg2+ handling in physiological conditions. Further studies
are needed to investigate thoroughly the hormonal regulation, the interacting partners, the
intracellular signaling pathways and the posttranscriptional events that modulate the activity
of the currently known magnesiotropic proteins.
In the future, the successful collaboration between
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S. FERRÈ ET AL.
clinical geneticists and renal physiologists will
allow the identification of new disease genes and,
therefore, lead to the functional characterization
of additional molecular players involved in active,
renal Mg2+ transport.
Disclosure
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 07/05/2017.
This work was supported by the Netherlands
Organization for Scientific Research (ZonMw
9120.6110, 9120.8026, NWO ALW 818.02.001)
and a European Young Investigator award
(EURYI) 2006.
None of the authors has any conflict of interest
to disclose.
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