Pediatr Nephrol (2001) 16:412416

IPNA 2001

E X P E R I M E N TA L S T U D I E S / O R I G I N A L A R T I C L E

Yosef S. Haviv Hanna Wald Moshe Levi

Michal Dranitzki-Elhalel Mordecai M. Popovtzer

Late-onset downregulation of NaPi-2

in experimental Fanconi syndrome

Received: 21 August 2000 / Revised: 18 December 2000 / Accepted: 22 December 2000

Abstract The pathogenesis of renal phosphate (Pi) leak

in Fanconi syndrome is unknown. Disorders of apical
membrane transporters, leaky apical membrane, depleted
cellular Pi and ATP, and impaired sodium (Na) pumps
have been proposed as underlying defects. The present
study examined the role of type II Na-Pi cotransport
system (NaPi-2) in experimental Fanconi syndrome in
rats. Following a single injection of maleic acid (MA),
75 mg/kg body weight IP, rats were sacrificed after
90 min, 4 h, and 24 h. Renal cortical expression of
NaPi-2 mRNA was determined by Northern blotting, and
brush border membrane (BBM) NaPi-2 protein by
Western blotting. Increased urinary excretion of phosphate was demonstrated as soon as 90 min after MA injection, and was sustained at 4 and 24 h. NaPi-2 mRNA
expression and NaPi-2 protein were not decreased after
90 min. NaPi-2 mRNA decreased after 4 h, while NaPi-2
protein decreased only at 24 h. Hence, the immediate
phosphaturia in experimental Fanconi syndrome may be
independent of NaPi-2 downregulation, possibly resulting from energy depletion or membrane dysfunction.
The decrease in NaPi-2 mRNA expression and the subsequent NaPi-2 protein decrease may account for the
second-phase phosphaturia.
Keywords Fanconi syndrome Proximal tubule
Phosphate transport Brush borders NaPi-2 mRNA
NaPi-2 protein

Y.S. Haviv H. Wald M. Dranitzki-Elhalel M.M. Popovtzer ()

Nephrology and Hypertension Services,
Hadassah-Hebrew University Medical Center,
POB 12000, Jerusalem, Israel 91120
e-mail: popovtzer@hadassah.org.il
Tel.: +972-2-6776881, Fax: +972-2-6427805
M. Levi
The University of Texas Southwestern Medical Center and VAMC,
Dallas, Texas, USA

Introduction
Inorganic phosphate (Pi) is the most-abundant intracellular anion and is essential for normal cellular metabolism
and energy production. Regulation of serum Pi within a
narrow range is dependent on effective transcellular
transport systems. The renal tubules are a major determinant of Pi homeostasis, and are subject to hormonal and
dietary modulation [1]. The proximal tubule is the major
site of Pi reabsorption, where unidirectional Pi transport
involves uptake from the lumen across brush border
membrane (BBM) and efflux at the basolateral membrane [2]. BBM Pi uptake is the rate-limiting step in
renal Pi reabsorption, thereby being a primary site for
regulation. This regulation is mediated by apical Na-Pi
cotransporters and basolateral Na-K-ATPase that maintain a gradient for intracellular Na influx. Pi efflux
across the basolateral membrane is probably passive and
may involve anion exchange [3].
There are three types of Na-Pi cotransporters. Type I
and type II are expressed mainly in the kidney, while
type III is ubiquitous and may serve for housekeeping
Na-Pi cotransport. Type II is the most abundant and may
account for 85% of Pi reabsorption. Type II Na-Pi
cotransporter mRNA is expressed exclusively in the
proximal convoluted tubule, and its immunoreactive
protein is localized to the BBM [4, 5]. The dominant role
of Na-Pi 2 is demonstrated in murine gene-knockout
models of NaPi-2, where massive phosphaturia occurs
along with reduced BBM Na-Pi cotransport [6].
Na-Pi II is the major target for parathyroid hormone
(PTH) regulation. PTH induces endocytosis and retrieval
of NaPi-2 from the BBM and lysosomal degradation of
the protein. Therefore, recovery of NaPi-2 after the effect
of PTH requires de novo synthesis of the protein [4, 5].
Acute alterations in dietary Pi intake also inversely
affect NaPi-2 post-transcriptionally by recruiting pre-existing NaPi-2 protein to the apical membrane, or its retrieval and degradation, respectively [4, 5].
Maleic acid (MA) produces an experimental Fanconi
syndrome (FS) characterized by rapid bicarbonaturia,

413

natriuresis, and kaliuresis. Aminoaciduria, glycosuria,

and phosphaturia ensue, but their mechanism remains
elusive. Bicarbonaturia is probably associated with inhibition of the Na+/H+ antiporter and the electrogenic
Na-independent H+-ATPase. These defects may follow
reduced activity of Na+-K+-ATPase, abnormal proximal
tubular cell membrane permeability, ATP depletion, and
impaired cytosol-membrane trafficking [7, 8]. However,
some of the previous studies on MA-induced FS used
very high doses of MA, possibly leading to a generalized
tubular cellular toxicity and obscuring the specific mechanism of Pi leak. The purpose of this work was to characterize the NaPi-2 changes in the renal cortex during
the development and recovery from MA injury to better
define the molecular mechanisms of experimental FS,
and to correlate the observed changes in NaPi-2 with
alterations in renal tubular phosphate transport.

15 min of immersion in boiled 1x standard sodium citrate plus

0.1% sodium dodecyl sulfate (SDS), and the same membranes
were hybridized with a control probe of 18-S ribosomal RNA.
The radioactive probes were prepared with Rediprime DNA
labeling kit (Amersham) using ECO-1 fragment of full-length
cDNA probe of NaPi-2, and a cloned fragment of 18-S ribosomal
RNA as template. Binding was quantified by phosphorimaging
(Fujis, BAS 1000) and expressed as the ratio of intensities obtained by hybridizing the same strip with NaPi-2 and 18-S.
Preparation of BBM
Kidneys were rapidly removed from the rats and slices were cut at
4C from the superficial cortex, homogenized in a buffer consisting of 300 mM DL-mannitol, 5 mM EGTA, 16 mM Hepes, and
10 mM TRIS, pH 7 l.5, containing protease inhibitor cocktail tablets (Boehringer, Mannheim, Germany). BBM were precipitated
from the homogenate by magnesium precipitation and differential
centrifugation. The final pellet was suspended in the same buffer
as above. The protein concentration of the BBM preparation was
determined by an automated pyrogallol red colorimetric method
(Cobas Mira Roche, Basel, Switzerland).

Materials and methods

Animals
Male Wistar rats weighing 200 g were put in metabolic cages
for 24 h for adaptation. The animals had free access to normal
laboratory chow and were given tap water to drink ad libitum. MA
(Sigma, St. Louis, Mo., USA) was dissolved in isotonic saline and
the pH of the solution was increased to 7.2 with 5 M sodium
hydroxide. The solution was injected once intraperitoneally (IP),
75 mg/kg body weight, i.e., 1.5 ml of a 250 mM solution of MA/
100 g body weight. A larger dose resulted in a polyuric acute renal
failure (ARF), while a smaller dose did not result in a complete FS.
Control rats were injected with the same volume of normal saline.
Because of massive diuresis following MA injection [2 ml after
90 min (group I), 5 ml after 360 min (group II), and 2025 ml after
24 h (group III) vs. 5 ml/day for normal rats], normal saline was injected IP (2 ml for group I, 5 ml for group II, and 20 ml, divided into
two doses, for group III) in the study groups. These IP normal saline
boluses prevented the ARF that rats developed when injected only
with MA. Urine was collected and analyzed for Na, potassium, phosphate, calcium, and creatinine. After MA injection (90 min, 360 min,
and 24 h) rats were anesthetized with ether and sacrificed by aortic
puncture. After blood was sampled, both kidneys were immediately
removed and processed for Northern and Western blotting.
Metabolic studies
Following adaptation to metabolic cages, 24-h urine samples and
blood samples were analyzed for Na, potassium, phosphate, calcium, and creatinine. Blood was collected immediately before sacrifice and analyzed for pH, bicarbonate, Na, potassium, phosphate,
calcium, and creatinine.
Northern blots
Total RNA was isolated from renal cortex immediately after sacrifice, using a Tri-reagent kit (Molecular Research Center, Cincinnati, Ohio, USA). Aliquots of 1020 g total RNA were resolved
electrophoretically on 1% agarose gels under denaturing conditions
(formamide/formaldehyde). Nucleic acids were transferred to nylon membranes (Gene Screen, New England Nuclear Research
Products, Boston, Mass. USA) and cross-linked by ultraviolet
irradiation. Membrane strips were hybridized for 1620 h with
32P-labeled rat specific NaPi-2 cDNA, under stringent conditions.
Membranes were washed and autoradiography was performed by
standard procedures. Bound cDNA probes were removed by

SDS-polyacrylamide gel electrophoresis and immunoblotting

Aliquots of BBM were denatured 1:1 with sample buffer containing 4% SDS, 20% glycerol, 1% -mercaptoethanol, and 125 mM
TRIS-HCl, pH 6.8; 60 g of BBM protein per lane was separated
on 10% polyacrylamide gels and electrotransferred onto nitrocellulose paper. After blocking with 5% fat-free milk powder, the
blots were incubated with antiserum against the C-terminal amino
acid sequence of NaPi-2 at a dilution of 1:5,000. Secondary antibodies consisted of goat anti-rabbit IgG diluted to 1:10,000. Antibody binding was visualized with enhanced chemiluminescence,
and quantified by densitometry.
Statistics
Results are expressed as meanSEM. Statistical significance between control and MA-treated rats was determined by non-paired
Students t-test or one-way analysis of variance (ANOVA) with
Student Newman Keuls analysis.

Results
Serum and urine biochemical data are shown in Tables 1
and 2. These studies demonstrate the characteristics of FS,
namely phosphaturia, metabolic acidosis, and kaliuresis.
Random urine spot tests with Albustix were qualitatively
positive for glycosuria in rats given MA, and were negative in the control group. The administration of MA was
associated with an immediate onset of polyuria. While
mean urine output was 56 ml/24 h for control rats, animals administered MA produced 2530 ml of urine/day.
By 4 h following MA, the urine output was already of the
same magnitude as that of control rats over a 24-h period.
Phosphaturia was documented as early as 90 min following MA injection. Despite subsequent hypophosphatemia, phosphaturia was evident for at least 24 h after the
initial insult. As shown in Table 1, hypophosphatemia is
most pronounced after 90 min and 24 h, while after 4 h a
trend towards a better Pi conservation is observed. Hence,
we observed two phases of Pi excretion. The first phase
demonstrated an acute onset of phosphaturia occurring

414
Table 1 Serum biochemical
tests after maleic acid (MA)
injection

*P<0.05 vs. control,

**P<0.01 vs. control

Control (n=4)
90 min (n=5)
4 h (n=6)
24 h (n=5)

Table 2 Fractional excretion of

Pi after MA injection

*P<0.001 vs. control

Control (n=4)
90 min (n=5)
4 h (n=6)
24 h (n=5)

Sodium
(mEq/l)

Potassium
(mEq/l)

Phosphate
(mEq/l)

Calcium
(mEq/l)

Bicarbonate
(mEq/l)

145.52
140.44
1423
141.52

3.70.4
2.80.2
3.350.4
2.50.2*

2.90.2
1.710.1**
2.190.2*
1.580.1**

5.550.3
5.450.3
5.420.2
5.230.2

240.8
19.50.5**
18.20.8**
15.40.7**

Pi clearance
(ml/min)

Creatinine clearance
(ml/min)

Fractional excretion
of Pi

0.0450.002
0.9250.04*
0.460.02*
0.540.02*

1.450.03
1.260.05
1.460.04
1.20.07

3%0.06
73.4%2*
31%1*
45%1*

Fig. 1a, b NaPi-2 mRNA expression in experimental Fanconi

syndrome. a A representative Northern blot. b A bar graph of
mean results of at least four rats (n is given in Table 3)

Fig. 2a, b NaPi-2 brush border membrane (BBM) protein in experimental Fanconi syndrome. a A representative Western blot. b A
bar graph of mean results of at least four rats (n is given in Table 3)

within 90 min and partially compensated within 4 h, while

the late-onset phosphaturia persisted for at least 24 h.
Table 2 shows a remarkably high fractional excretion of
Pi (73%) manifested as early as 90 min after exposure to
MA. This diffuse Pi leak decreases by 50% 2.5 h later,
only to recur, although to a lesser degree, after 24 h.
The transient resolution of the tubular insult at 4 h
was not limited to Pi handling. Potassium levels were
also corrected towards normal after 4 h, but decreased
again within 24 h. Serum calcium levels were kept
within a remarkably narrow normal range in all phases,
unaffected by hypophosphatemia or mild renal failure.
A mild reduction in the glomerular filtration rate
(GFR) was evident after 90 min. This reduction may
have occurred directly because of polyuria and hypovolemia, or it may reflect a functional glomerular impairment secondary to renal parenchymal toxic injury.
Early hypophosphatemia and phosphaturia reflect impairment of Pi transport. While NaPi-2 mRNA expres-

Table 3 Renal cortical expression of NaPi-2 mRNA by Northern

blotting and brush border membrane NaPi-2 protein by Western
blotting (in arbitrary densitometry units)

Control
90 min after MA
4 h after MA
24 h after MA

NaPi-2 mRNA

NaPi-2 protein

35.26.9 (n=4)
34.05.8 (n=5)
16.62.9 (n=5)*
9.82.9 (n=5)**

1.350.17 (n=9)
1.630.2 (n=4)
1.360.49 (n=4)
0.270.04 (n=5)***

*P<0.05 vs. control, **P<0.01 vs. control, ***P<0.001 vs. control

sion was intact 90 min after exposure to MA, it declined

2.5 h later (Fig. 1). As shown in Table 3 and Fig. 1,
NaPi-2 mRNA expression is inhibited progressively for
24 h by a single injection of MA. However, BBM NaPi-2
protein abundance remained intact 90 min and 4 h after
injection of MA (Fig. 2). This reflects a discrepancy between the reduced activity of the NaPi-2 cotransporter

415

and its abundance in the BBM. The abundance of NaPi-2

protein decreased only later, between 4 and 24 h after
MA injection. Hence, Pi transport activity is the first to
be inhibited by MA, followed by NaPi-2 mRNA expression, while BBM NaPi-2 protein abundance is the last to
be negatively affected.

Discussion
In kidneys of MA-treated rats, evidence of injury is
observed immediately after MA administration, which
progresses to extensive necrosis of the proximal tubules
by 24 h, while the loops of Henle and distal convoluted
tubules remain intact [9]. A disorder in Na gradientdependent solute uptake of renal BBM may be one of the
underlying mechanisms of experimental FS [10]. However, other studies suggested that FS induced by maleate
is not caused by an inhibition of BBM Na+-dependent
transport systems, but that protein phosphorylation may
play an important role in the molecular defect involved
in FS [11].
In the model used in this study, a rapid generalized
proximal injury induced by MA was evident by the rapid
onset of kaliuresis, metabolic acidosis, phosphaturia, and
glycosuria. MA administration to experimental animals
induces a rapid, reversible, complex dysfunction of
the renal tubule resembling FS. A defect in the proximal
tubule Na+-K+-ATPase appears to play a role in MAinduced FS [12]. Na-K-ATPase is the biochemical correlate of active cellular transmembrane sodium transport.
The transient early phosphaturia, independent of NaPi-2
protein abundance, may reflect the partial recovery of
Na-K pump activity and amino acid oxidation, well
known to occur after MA administration [12].
Another feature of the early, diffuse, and reversible
generalized proximal tubular injury may be the intracellular Pi depletion. This Pi depletion may affect membrane-bound, insoluble Pi in the proximal tubule, which
may interfere with proximal tubular transport [6]. While
Na+/H+ antiporter may induce only bicarbonaturia, extensive energy depletion may cause a generalized leak.
Pi infusion attenuates MA-induced bicarbonaturia [8,
13], while metabolic acidosis induced by MA worsens
renal tubular leak as intravenous bicarbonate infusion,
which corrects the metabolic acidosis, reduces the fractional excretion of Pi [13].
The time-scale of these effects of MA are of unique
significance. Our results suggest two phases of phosphaturia: a rapid phosphaturia, independent of NaPi-2, and a
late-onset inhibition of NaPi-2-dependent proximal tubular Pi reabsorption. Experimental FS may exhibit a complete inhibition of Na-dependent phosphate uptake by renal BBM vesicles, decreased ATP production by the renal tubule, and a reversible effect on renal mitochondria
[14]. The abnormal appearance of the mitochondria, with
compressed crystal membranes and flocculent densities,
is one of the most-impressive findings in MA-associated
FS [9]. Therefore, the early phase of phosphaturia may

reflect a non-specific energy depletion, resulting in Pi

transport failure despite intact BBM NaPi-2 protein.
Indeed, in a previous study from our laboratory we
have shown in the same model a marked reduction in
ATP content in cortical slices [15]. This mechanism may
involve the inhibition of Na-K-ATPase activity, immediately resulting in failure of active cellular transmembrane Na pumping out of proximal convoluted tubules
and failure of Na-dependent transport processes. Furthermore, Kramer and Gonick [16] and later Mujais [12]
demonstrated inhibition of the Na pump in the renal cortex in the same model of experimental FS.
A different theory was presented by Bergeron et al.
[17] who performed a series of elegant experiments
using microinjection techniques that demonstrated that
experimental Fanconi syndrome can be explained by a
modification of the cell membrane (increased efflux) at
the distal sites of the nephron rather than by modification
of the membrane transport (decreased influx) at the proximal sites. They demonstrated normal entry of labeled
amino acids and phosphate from the luminal side of the
proximal tubule cell, consistent with normal brush border uptake of phosphate. This is compatible with our
finding of normal NaPi-2 protein expression at 90 min
and 4 h.
Alternatively, a specific effect on gp330 may also be
involved. This apical membrane glycoprotein functions
as a receptor associated with the apical endocytotic and
recycling apparatus in proximal tubular cells. The generalized membrane transport derangement seen in this experimental FS could also theoretically result from blocking endocytosis and/or the recycling of the NaPi-2 protein [18].
Phosphaturia itself may have a role in propagating the
proximal tubule injury, as evident by attenuation of bicarbonaturia by a prior Pi infusion [7, 8, 12]. Pi infusion
also restores Na+-K+-ATPase activity, suggesting a role
of a primary cellular energy failure in the late effects of
experimental FS [8].
We suggest that because the early phase of MA-induced phosphaturia is apparent within minutes of injection, the inhibition cannot reflect alterations in NaPi-2
transporter synthesis or degradation but has to be functional, such as phosphorylation or some other modification of the NaPi-2 cotransporter protein. This hypothesis
is supported by this study demonstrating the discrepancy
between functional Pi transport failure and the intact
NaPi-2 mRNA and NaPi-2 protein within 90 min of MA
injection.
The second phase of phosphaturia, however, may be
more specific and occurs following interference with
NaPi-2 transcription and translation, or following interruption of cytosolic trafficking of the protein to the proximal convoluted tubule membrane. We showed that lateappearing phosphaturia in MA-induced FS is associated
with decreased NaPi-2 cotransporter mRNA expression
that may directly affect the BBM Pi transport capacity. A
primary energy depletion may also play a role in the late
inhibition of NaPi-2 transcription and translation. Hypo-

416

phosphatemia is normally a strong stimulator of NaPi-2

mRNA expression and BBM NaPi-2 protein synthesis,
leading to enhanced proximal tubule Pi reabsorption and
reduced fractional excretion of Pi [4]. However, this
study demonstrated ongoing phosphaturia accompanied
by decreased NaPi-2 mRNA and NaPi-2 protein expression. Hence, the decrease in NaPi-2 mRNA expression
may account for the late-onset Pi leak. Inhibition of
NaPi-2 mRNA expression, decreased NaPi-2 protein
synthesis, or impaired trafficking and/or increased degradation, may lead to decreased BBM NaPi-2 protein expression. The late effects of heavy metal-induced FS are
also manifested by functional lesions at the BBM [19].
These effects may be observed only 2 days or more after
exposure, suggesting the inhibition of protein synthesis.
These mechanisms, well documented for heavy metals,
may also be involved in MA-induced FS.
Potassium and bicarbonate levels were also almost
normalized after 4 h, but decreased again within 24 h.
Thus the effect of MA on renal tubular function may be
dual, comprising two distinct functional impairments; an
acute non-specific metabolic insult and a late-onset
transport defect. Moreover, a failure of one transporter
may enhance another functional impairment, as can be
observed in an increased fractional excretion of Pi in
acidosis [12].
Normal levels of serum calcium suggest that the
mechanism involved in phosphaturia may be a primary
tubular dysfunction rather than hormonal. In fact, PTH
does not affect phosphaturia in MA-induced FS, while
25-hydroxyvitamin D3 may have an antiphosphaturic
effect [20]. Previous studies demonstrated renal refractoriness to PTH in maleate-induced FS in rats, although
adenylate cyclase activation remains intact [15].
A transient reduction of the GFR was observed after
90 min and 4 h of MA injection. This effect is a wellknown complication of MA and can be attenuated by an
infusion of isotonic saline [20]. A decrease in GFR accentuates the massive phosphaturia, as may be observed
in an abnormally high fractional excretion of Pi, indicating a direct tubular injury, regardless of GFR. Furthermore, the fractional excretion of Pi that negates the
effect of the GFR also demonstrates two phases of
phosphaturia (Table 2).
In conclusion, this study demonstrates a dual effect
of MA in the induction of FS. The first phase, occurring within 90 min, involves a rapid, NaPi-2 mRNA
and NaPi-2 protein-independent failure of proximal
tubular reabsorption, probably reflecting a functional
impairment. This functional dysfunction may involve
changes in Na-K pump activity, oxidative metabolism,
intracellular Pi, and/or phosphorylation or chemical
modification of NaPi-2 protein. However, the second
phase may involve the inhibition of NaPi-2 mRNA expression and NaPi-2 protein abundance, thereby inhibiting Pi handling by the renal cortical proximal tubule
cell. This study may therefore form a basis for understanding the effects of MA in causing two phases of
phosphaturia.

Acknowledgements These studies were supported by grants from

the Lillian and Stanley Willen Endowment Fund for Nephrology
Research to M.M. Popovtzer, VA Merit Review and NKF to
Moshe Levi.

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