The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a.

Abstract

Adaptor proteins containing PDZ interactive domains have been recently identified to regulate the trafficking and activity of ion transporters and channels in epithelial tissue. In the renal proximal tubule, three PDZ adaptor proteins, namely NHERF-1, NHERF-2 and PDZK1, are expressed in the apical membrane, heterodimerize with one another, and, at least in vitro, are capable of binding to NHE3 and Npt2a, two major regulated renal proximal tubule apical membrane transporters. Studies using NHERF-1 null mice have begun to provide insights into the organization of these adaptor proteins and their specific interactions with NHE3 and Npt2a. Experiments using brush border membranes and cultured renal proximal tubule cells indicate a specific requirement for NHERF-1 for cAMP-mediated phosphorylation and inhibition of NHE3. NHERF-1 null mice demonstrate increased urinary excretion of phosphate associated with mistargeting of Npt2a to the apical membrane of renal proximal tubule cells. NHERF-1 null animals challenged with a low phosphate diet and proximal tubule cells from these animals cultured in a low phosphate media fail to adapt as well as wild-type mice. These studies indicate a unique requirement for NHERF-1 in cAMP regulation of NHE3 and in the trafficking of Npt2a.

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J Physiol 567.1 (2005) pp 27–32
27
SYMPOSIUM REPORT
The role of NHERF-1 in the regulation of renal proximal
tubule sodium–hydrogen exchanger 3 and
sodium-dependent phosphate cotransporter2a
Edward J. Weinman1,2,3Rochelle Cunningham1, James B. Wade2and Shirish Shenolikar4
1Department of Medicine and2Department of Physiology University of Maryland School of Medicine;3Medical Service, Department of Veterans Affairs
Medical Center, Baltimore, MD 21201, USA
4Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Adaptor proteins containing PDZ interactive domains have been recently identified to regulate
the trafficking and activity of ion transporters and channels in epithelial tissue. In the renal
proximal tubule, three PDZ adaptor proteins, namely NHERF-1, NHERF-2 and PDZK1, are
expressed in the apical membrane, heterodimerize with one another, and, at least in vitro,
are capable of binding to NHE3 and Npt2a, two major regulated renal proximal tubule apical
membrane transporters. Studies using NHERF-1 null mice have begun to provide insights into
theorganizationoftheseadaptorproteinsandtheirspecificinteractionswithNHE3andNpt2a.
Experiments using brush border membranes and cultured renal proximal tubule cells indicate
a specific requirement for NHERF-1 for cAMP-mediated phosphorylation and inhibition of
NHE3. NHERF-1 null mice demonstrate increased urinary excretion of phosphate associated
with mistargeting of Npt2a to the apical membrane of renal proximal tubule cells. NHERF-1
null animals challenged with a low phosphate diet and proximal tubule cells from these animals
culturedinalowphosphatemediafailtoadaptaswellaswild-typemice.Thesestudiesindicatea
uniquerequirementforNHERF-1incAMPregulationofNHE3andinthetraffickingofNpt2a.
(Received 16 March 2005; accepted after revision 27 May 2005; first published online 2 June 2005)
CorrespondingauthorE.J.Weinman:DepartmentofMedicine,DivisionofNephrology,UniversityofMaryland,School
of Medicine, 22, South Greene Street, Baltimore, MD 21202, USA.Email: eweinman@medicine.umaryland.edu
The abundance and activity of epithelial transporters and
ion channels is tightly regulated and it is likely that these
membrane proteins exist as multiprotein complexes. Our
recent work has focused on the organization of three
PSD-95/Drosophila Discs large/ZO-1 (PDZ) adaptor
proteins,namelytheNa+–H+exchangerregulatoryfactor
or NHERF-1, NHERF-2 and PDZK1 in the regulation
and targeting of the sodium–hydrogen exchanger
isoform3 (NHE3) and the sodium-dependent phosphate
transporter2a(Npt2a),
transport proteins in renal proximal convoluted tubule
cells.
In 1995 we isolated and cloned a protein that
was a necessary cofactor for cAMP regulation of
NHE3 activity initially called NHERF (also known as
two importantregulated
This report was presented at The Journal of Physiology Symposium on
PDZ domain scaffolding proteins and their functions in polarized cells,
SanDiego,CA,USA,4April2005.ItwascommissionedbytheEditorial
Board and reflects the views of the authors.
ezrin-binding phosphoprotein of 50kDa (EBP50)), later
renamed NHERF-1 (Weinman et al. 1993, 1995). A
second member of the NHERF family was identified,
NHERF-2 (also known as NHE-3 kinase A-regulatory
protein (E3KARP), tyrosine kinase activator-1 (TKA1),
and sex-determining region of the Y chromosome
(SRY-1)-interacting protein-1 (SIP-1)) in a yeast 2-hybrid
screen using the NHE3 C-terminus as bait (Yun et al.
1997). NHERF-1 and NHERF-2 are encoded by unique
genes, contain no recognizable catalytic domains, and
share approximately 52% over all amino acid homology.
They are considered members of a protein family by
virtue of their common modular structure with two
tandemPDZhomologydomainsandaC-terminaldomain
that binds all members of the ezrin–radixin–moesin
(ERM) family of structural proteins (Reczek et al. 1997).
PDZK1 (PDZ containing 1, also known as NaPiCap1 or
CAP70) was identified using differential display PCR in
studies of phosphate-deprived rats. PDZK1 contains four
PDZ domains but unlike the NHERF proteins, lacks the
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28E. J. Weinman and others
J Physiol 567.1
C-terminal ERM domain (Custer et al. 1997). NHERF-1,
NHERF-2 and PDZK1 are expressed in the apical side
of renal proximal tubule cells and in the small intestines
(Wade et al. 2001, 2003). NHERF-1 and NHERF-2 form
homodimers and all three proteins heterodimerize with
one another (Fouassier et al. 2000; Lau et al. 2001;
Shenolikar et al. 2001; Gisler et al. 2003). It has been
proposed that they array a microvillar/submicrovillar
mesh or scaffold that regulates its target proteins. NHE3
and Npt2a appear to bind to all three of these adaptor
proteins (Lamprecht et al. 1998; Zizak et al. 1999; Gisler
etal.2001;Hernandoetal.2002).Avexingquestionrelates
to whether NHERF-1, NHERF-2 and PDZK1 represent
a redundant physiological control mechanism, function
independently of one another, or act cooperatively in the
regulation of target proteins.
Inthisreview,wewilltracetheevolutionofourthinking
about the role of NHERF-1, NHERF-2 and PDZK1 in the
regulation of NHE3 and Npt2a, and the renal tubular
reabsorption of sodium and phosphate. We initially
believedtheseadaptorproteinshadoverlappingfunctions
basedonresultsfrommodelcellsystems(Yunetal.1997).
Our more recent experiments, particularly studies using
NHERF-1 null mice, have led us to consider that the
organization of these adaptor proteins in native tissues
such as the renal proximal tubule importantly influences
theregulationofNHE3andNpt2a(Shenolikaretal.2002).
These studies highlight the fact that model cell systems,
whileprovidingimportantinformationaboutbiochemical
interactions between proteins, must be supported by
studies in native tissues where the interactions between
these adaptor proteins and their targets may differ.
NHERF-1, NHERF-2 and the regulation of NHE3
in PS120 cell fibroblasts
Initial study of the cellular function of NHERF-1 and
NHERF-2 was undertaken in PS120 cell fibroblasts, a cell
line negatively selected to express no endogenous NHE
activity (Yun et al. 1997). This cell line also does not
expressendogenousNHERF-1orNHERF-2.RabbitNHE3
was readily expressed in these cells but treatment with
cAMPfailedtoregulateNHE3activity.WhenNHERF-1or
NHERF-2 were coexpressed with NHE3, however, cAMP
inhibition of NHE3 activity was observed. These studies
established that NHERF-1 or NHERF-2 was required for
protein kinase A (PKA) associated down-regulation of
NHE3 activity. The biochemical bases for the effect of the
NHERFproteinswaselucidatedbythedemonstrationthat
NHERF-1 and NHERF-2 bound to NHE3 and to ezrin.
Ezrin,actingasaproteinkinaseAanchorprotein,recruited
PKA thereby facilitating the rapid phosphorylation of
specific serine residues in the C-terminus of NHE3 with a
consequent down-regulation of the activity of the trans-
porter(Lamprechtetal.1998;Zizaketal.1999).Themodel
that emerged was that the NHERF proteins were required
for the formation of a multiprotein complex and that the
bindingofNHERFtobothNHE3andezrinwascriticalfor
thistypeofhormonalregulation(Weinmanetal.2000).In
PS120cells,NHERF-1andNHERF-2wereequallyeffective
in mediating cAMP inhibition of NHE3 activity (Yun
et al. 1997).
Localization of NHERF-1 and NHERF-2 in the kidney
of rodents and man
Highly specific antipeptide antibodies that differentiated
NHERF-1 from NHERF-2 were used to determine the
tissue distribution of the NHERF isoforms. Initial studies
were performed using the rat kidney (Wade et al. 2001).
Although both isoforms were detected in specific cells of
the nephron, NHERF-1 but not NHERF-2 was readily
detected in the apical membrane of renal proximal tubule
cells and we suggested that NHERF-1 was the relevant
isoformmediatinghormonalregulationofNHE3activity.
Additional studies in man and mouse, however, indicated
thepresenceofbothNHERFisoformsintherenalproximal
tubule(Wadeetal.2003;Weinmanetal.2003b).Asshown
in Fig.1, the distribution of NHERF-1 and NHERF-2
in mice was not identical. NHERF-1 was expressed in
the microvillar membrane and colocalized with NHE3
and Npt2a. NHERF-2, on the other hand, was expressed
predominantly in the submicrovillar region of renal
proximaltubulecellsbutonlyminimallyinthemicrovillus
itself. This distribution was confirmed using immuno-
gold staining and electron microscopy. The factors
that determine the unique distribution of the NHERF
isoformsareunknownbutwhenconsideredfromaphysio-
logical perspective, the findings that both NHERF-1 and
NHERF-2 were expressed in renal proximal tubule cells
necessitated a reconsideration of the question of the roles
of these proteins in control of NHE3 and Npt2a activity
and abundance.
Development of the NHERF-1−/−mouse
The potential complexity of the interactions between
NHERF-1 and NHERF-2 with each other and with other
PDZ scaffolding proteins in renal cells suggested that a
genetic approach would be required to determine the
individual role of each of these proteins on sodium and
phosphate transport in the proximal tubule of the kidney.
Using homologous recombination and a vector targeting
exon 1 of the mouse NHERF-1 gene, we successfully
abolished NHERF-1 expression in all mouse tissues
(Shenolikaretal.2002).MaleNHERF-1−/−micedisplayed
no overt phenotype. Blood pressure, serum electrolytes,
renal function and renal histology were normal. However,
mutantmalemicedemonstratedmildhypophosphatemia
and, as compared with wild-type mice, increased urinary
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NHERF-1 and regulation of renal proximal tubule NHE3 and Npt2a 29
excretion of phosphate. Some, but not all, NHERF-1 null
female mice were runts, displayed severe osteoporosis
and bone fractures, and died shortly after weaning. The
more normal appearing females were used for breeding to
establish an NHERF-1 null mouse colony. The availability
of NHERF-1−/−mice permitted an assessment of the
relative contribution of NHERF-1 and NHERF-2 to the
regulation of NHE3 and Npt2a.
NHERF-1 uniquely regulates cAMP-associated
inhibition of NHE3 activity
As determined using tissue fractionation and confocal
microscopy, the expression of NHE3 in the renal
apical membrane did not differ between wild-type and
NHERF-1−/−micesuggestingthatNHERF-1didnotaffect
thetraffickingofNHE3(Shenolikaretal.2002).Moreover,
the abundance and cellular distribution of NHERF-2 was
not affected by the absence of NHERF-1 (Shenolikar
et al. 2002; Weinman et al. 2003a; Cunningham et al.
Figure 1. The distribution of NHERF-1 and NHERF-2 in the renal proximal tubule of wild-type mice
A, representative confocal images of proximal convoluted tubules of the mouse kidney using antibodies specific
for NHERF-1 (a) and NHERF-2 (b). c is the merged images showing the localization of NHERF-1 in the microvillar
membranes and NHERF-2 predominantly in a region just below the microvilli. B, electron microscopical images of
wild-type renal proximal tubules using immunogold showing the localization of NHERF-1 in the microvillus (a) and
NHERF-2 in vesicle-rich region at the base of the microvilli (b). (Figures adapted from Wade et al. 2003.)
2004). To study the role of NHERF-1 in the regulation
ofNHE3activity,brushbordermembranevesicles(BBM)
were harvested from wild-type and NHERF-1 null mice,
PKA was activated ex vivo, and NHE3 activity was
measured as the amiloride inhibitable component of
pH gradient-stimulated uptake of sodium (Weinman
et al. 2003c). Basal NHE3 activity did not differ between
wild-type and knockout BBM consistent with the finding
that the abundance of the transporter was not altered
in NHERF-1 null mice. Activation of PKA resulted in
a 50% decrease in NHE3 activity in wild-type BBM
but failed to affect the activity of the transporter in
NHERF-1−/−membranes. The defect in the regulation
of NHE3 in NHERF-1 null renal BBM was associated
withthelackofPKA-mediatedphosphorylationofNHE3,
the biochemical signature of this form of regulation,
despite the presence of normal amounts and activity of
BBM PKA. The abundance of NHERF-2 and PDZK1 also
was not different. We concluded that NHERF-1 uniquely
transduces the cAMP signals that inhibit NHE3 activity
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J Physiol 567.1
and that NHERF-2 and PDZK1 could not substitute for
the absence of NHERF-1.
ThesestudieswereextendedtomeasurementsofNHE3
activity in cultured renal proximal tubule cells from
wild-typeandNHERF-1nullanimals(Cunninghametal.
2004).PTHstimulatedcAMPaccumulationandactivated
PKC to the same extent in both cell types. Basal NHE3
activity determined using fluorescence measurements
did not differ between the cell types but while PTH
and forskolin significantly inhibited NHE3 activity in
wild-typecells,neitherPTHnorforskolininhibitedNHE3
activity in NHERF-1 null cells. Infection of NHERF-1−/−
proximal tubule cells with adenovirus-GFP-NHERF-1
completelyrestoredtheinhibitoryeffectofPTHandcAMP
onNHE3activity.Thus,theseexperimentsestablishedthat
inrenaltissue,NHERF-1wasrequiredforcAMP-mediated
inhibition of NHE3 activity and that the effect of
NHERF-1, NHERF-2 and PDZK1 were not redundant,
as they appeared to be in transfected PS120 cells (Yun
et al. 1997).
NHERF-1 regulates renal brush border abundance
of Npt2a
Male and female NHERF-1−/−mice exhibit a decrease
in the serum concentration of phosphate, an increase
in the urinary excretion of phosphate, and a decrease
in the renal BBM expression of Npt2a, the major
regulated sodium-dependent phosphate transporter in
the proximal convoluted tubule (Shenolikar et al. 2002;
Murer et al. 2003; Bacic et al. 2004; Biber et al. 2004).
These results were consistent with expression studies in
OK cells, a proximal tubule cell line, where disruption
of binding of NHERF-1 to ezrin resulted in reduced
membrane expression of Npt2a (Hernando et al. 2002).
A physiological approach was undertaken to discern the
involvement of NHERF-1 in the regulation of Npt2a.
Wild-type mice rapidly decrease the urinary excretion of
phosphate when fed a diet low in phosphate (Weinman
et al. 2003a). This adaptive response is associated with
recruitment of Npt2a to the apical membrane of renal
proximal tubule cells. NHERF-1−/−mice also adapted
rapidly to dietary limitation of phosphate intake but, as
compared with wild-type mice, never adapted fully. This
was associated with decreased abundance of Npt2a in
the plasma membrane of the mutant mice and increased
detection of Npt2a in submicrovillar vesicular structures.
Wild-type proximal tubule cells in culture adapt
to growth in low phosphate media in a manner
analogous to restricting the dietary intake of phosphate
anddemonstrateincreasedsodium-dependentphosphate
uptake and BBM Npt2a abundance (Cunningham et al.
2004). By contrast, proximal tubule cells from NHERF-1
nullmicehavelowerratesofsodium-dependentphosphate
transport compared with wild-type cells and fail to
increase the rate of phosphate transport or Npt2a
abundance in response to growth in a low phosphate
media. The phosphate content of the media did not affect
the abundance of NHERF-1 in the plasma membrane
of wild-type cells and the abundance of NHERF-2 also
was not affected by the phosphate content of the media
in either wild-type or NHERF-1 null cells. Interestingly,
the abundance of PDZK1 in the plasma membrane of
culturedproximaltubulecellswashigherincellsgrownin
low phosphate media but the increase in abundance was
equivalent in wild-type and NHERF-1−/−cells.
Preliminary studies suggest that NHERF-1 is required
for the inhibition of sodium-dependent phosphate
transport and thedecrease
Npt2a abundance in response to parathyroid hormone
(R. Cunningham & E. J. Weinman, unpublished data).
It is likely that independent processes mediate the plasma
membranerecruitmentofNpt2ainresponsetophosphate
deprivation and the removal of Npt2a in response to
PTH. While NHERF-1 may be involved in both processes,
we have speculated that NHERF-1 functions as an
Npt2a membrane retention signal and that the absence
of NHERF-1 limits the amount of Npt2a capable of
remaining on the BBM.
inapical membrane
Perspectives
The interaction between NHERF-1 and NHE3 differs
significantly from its interactions with Npt2a. NHERF-1
formsacomplexwithNHE3affectingitsphosphorylation
in response to stimuli that activate PKA. The association
between NHE3 and NHERF-1 seems to occur within the
plasma membrane, and the binding is constitutive and
not affected by activation of PKA (Zizak et al. 1999). By
contrast,NHERF-1bindsNpt2aandaffectsthetrafficking
and tissue distribution of the transporter (Shenolikar
etal.2002).ThereisnoevidencethatNHERF-1affectsthe
phosphorylation state of Npt2a although this possibility
has not formally been excluded.
The role of NHERF-2 and PDZK1 on NHE3 and
Npt2a has been less well studied. NHERF-2 affects
calcium-mediated changes in NHE3 trafficking in model
cell systems (Lee-Kwon et al. 2003a,b). Npt2a also binds
to NHERF-2 in yeast 2-hydrid screens (Gisler et al. 2001).
In mice, we have observed that NHERF-2 and Npt2a
can be coimmunopreciptiated only from lysates of the
renal cortex from wild-type but not NHERF-1−/−mice
suggesting that the association between NHERF-2 and
Npt2awasindirectandrequiredthepresenceofNHERF-1
(Wade et al. 2003). The potential role of PDZK1 in the
regulation of NHE3 and Npt2a is not clear although
PDZK1 binds to both transporters (Gisler et al. 2003).
PDZK1 null mice manifest no overt defects in renal
phosphate transport or the expression of Npt2a when fed
a normal diet but exhibit differences from wild-type mice
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J Physiol 567.1
NHERF-1 and regulation of renal proximal tubule NHE3 and Npt2a31
whenchallengedwithahighphosphatediet(Kocher etal.
2003; Capuano et al. 2005). PDZK1 mRNA is increased
inresponsetophosphatedepletion,andwehaveobserved
a modest but significant increase in PDZK1 protein in
proximal tubule cells grown in low phosphate media
(Cunningham et al. 2004). It remains distinctly possible
that the adaptive response to low phosphate requires a
cooperative interaction between NHERF-1 and PDZK1.
Since the initial discovery of NHERF-1 and the
subsequent discoveries of NHERF-2, PDZK1, and other
adaptor proteins, there has been an evolution in our
thinking about how these proteins interact not only with
oneanotherbutalsowithtargetproteins.Wehavereviewed
our results and speculations with respect to NHE3 and
Npt2abuthavenotconsideredthemultipleothertargetsof
theseadaptorproteinsthatdirectlyorindirectlymayaffect
cell function (Voltz et al. 2001; Shenolikar et al. 2004). It
is our view that future studies will need to combine cell
expressionexperimentsinmodelcellsystemswithstudies
in intact tissues of appropriate animals. Recognizing the
cautions inherent in using genetically altered mice, the
development of NHERF-1, NHERF-2 and PDZK1 null
mice should provide the necessary models to decipher
the unique as well as the common roles of these adaptor
proteins.
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