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Departments of Physiology (A.I.A.), Anatomy (M.S., D.D.), Toxicology (R.M., V.S.), and Pharmacology (J.A.), University of Zaragoza, 50013 Zaragoza, Spain; Institute of Physiology (J.B., H.M.), University of Zürich-Irchel, CH-8057 Zürich, Switzerland; and Department of Internal Medicine (M.L.), University of Texas Southwestern Medical Center and Department of Veterans Affairs Medical Center, Dallas, Texas 75216
Address all correspondence and requests for reprints to: Víctor Sorribas, Ph.D., Departamento de Toxicología, Facultad de Veterinaria, Universidad de Zaragoza, Calle Miguel Servet, 177, E-50013 Zaragoza, Spain. E-mail: sorribas{at}posta.unizar.es
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Short-term regulation of Pi reabsorption is mainly mediated by PTH and alterations in dietary Pi intake, both mechanisms involving shuttling or recycling of Na/Pi cotransporter-containing vesicles between the cytoplasm and the brush border membrane (BBM). Long-term regulation includes many different hormonal and nonhormonal mechanisms that alter the cell content of the specific messenger RNA (mRNA) (3). To understand properly the complex network controlling Pi renal excretion/reabsorption, it is important to determine precisely the physiological role of each one of these regulatory mechanisms.
Because Pi is intensively used in general metabolism, Pi homeostasis should be regulated by factors controlling the rate of metabolism itself. One such factor is thyroid hormone, and its role in Pi reabsorption regulation has been extensively analyzed (4, 5, 6). Pharmacological doses of T3 have been shown to increase Na/Pi cotransport in BBM vesicles from rat proximal tubules (4, 5). In addition, T3 concentrations approximating the association constant (Km) of the thyroid hormone nuclear receptor also elicited a similar increase in Pi transport in opossum kidney (OK) cells (6). In both cases, the increase in transport rate was caused by an increase in the capacity of the transport system, whereas the affinity was not modified. Recently, Euzet et al. (8, 9) have shown an important role for T3 in the maturation of the renal Na/Pi cotransporter, which was associated with changes in both Km and Vmax, as well as in the recently cloned type II Na/Pi cotransporter (NaPi-2) (7) protein and mRNA abundance.
In the present study, we have determined the role of physiological concentration of thyroid hormone in renal phosphate transport in vivo; more exactly, the molecular mechanisms of enhancement of phosphate reabsorption by thyroid hormone. In addition, we have tried to determine the potential role of thyroid hormone in impairment of phosphate reabsorption that accompanies the aging kidney. Our results show that chronically treated hypothyroid rats, using a physiological dose of T3, exhibit increases in phosphatemia, NaPi-2 mRNA and protein content, and Na/Pi cotransport in superficial and juxtamedullary renal cortex, all these effects by means of enhanced transcription of the corresponding NaPi-2 gene. The stimulatory effect of the hormone is less evident in the aging kidney, which shows a lower level of basal phosphate reabsorption. In our experimental design, only pharmacological hyperthyroidism is able to restore partially the level of phosphatemia observed in young animals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thyroid hormone assays
T3 was measured in whole plasma by specific and
highly sensitive RIA, as described (11). The standard curve is prepared
using plasma from severely hypothyroid thyroidectomized rats, the limit
of detection being 15 ng T3/dl.
BBM preparations
On the day of the experiment and after CO2 narcosis,
blood was drawn from the aorta, and the kidneys were rapidly removed.
Thin slices were cut, at 4 C, from the superficial and juxtamedullary
cortex and were homogenized with a Disperser DIAX 600 (Heidolph,
Kelheim, Germany) in a buffer consisting of the following (in
mM): 300 DL-mannitol, 5 EGTA, 0.5 phenylmethylsulfonyl
fluoride, and 16 HEPES (pH 7.5 with Tris). BBM were purified from this
homogenate by Mg2+ precipitation and differential
centrifugation, as described (12). The final pellet was resuspended in
a buffer of 300 mM mannitol and 16 mM
HEPES-Tris (pH 7.5). Purity of BBM preparations was enzymatically
assayed as described (12).
Transport assays
Sodium gradient-dependent phosphate transport (Na/Pi
cotransport) measurements were performed, in freshly isolated BBM
vesicles, by uptake of 0.1 mM PO4 (a mix of
K2HPO4 plus KH2PO4, pH
7.4), plus K2H32PO4 (DuPont NEN Research Products, Boston, MA) as radio tracer (4 µCi/ml
uptake medium, 3,000 Ci/mmol) and an inwardly directed sodium gradient
(120 mM NaCl), followed by rapid filtration. Uptake was
measured at 10 sec, which still represents the initial linear phase of
phosphate transport at 25 C.
SDS-PAGE and immunoblots
Aliquots of superficial and juxtamedullary BBM vesicles were
denatured for 2 min at 95 C in 2% SDS, 10% glycerol, 0.5
mM EDTA, and 95 mM Tris-HCl (pH 6.8) (final
concentrations), and 10 µg BBM protein per lane were separated on
10% polyacrylamide gels according to the method of Laemmli (13) and
electrotransferred on nitrocellulose paper (14). Immunodetection with
antiserum against NaPi-2 (15) and sodium-sulfate cotransporter NaSi-1
(16) was performed by chemiluminescence using the BM Western Blotting
Kit from Boehringer Mannheim (Mannheim, Germany) and
visualized with x-ray films (Hyperfilm MP) from Amersham International (Buckinghamshire, UK). Image analysis and
quantification were done with a Gel Doc 1000 Video Gel Documentation
System (Bio-Rad Laboratories, Inc., Hercules,
CA).
Immunohistochemistry
These experiments were performed as described (10). Briefly,
anesthetized rats were perfused retrogradely with a fixative of
paraformaldehyde and picrinic acid, and 5-µm-thick sections were cut
at -20 C with a cryostat. Anti-NaPi-2 antibody was used at 1:500
dilution in PBS/milk powder buffer and detected with goat antirabbit
IgG antibody linked to Cy2 (Amersham International) at
1:200 dilution. In some experiments, ß-actin was visualized with
rhodamin-conjugated phalloidin (Sigma Chemical Co., St.
Louis, MO) at 1:500 dilution in PBS/milk powder. Sections were
coverslipped using mounting media plus 2.5%
1,4-diazabi-cyclo{2.2.2}octane (DABCO; Sigma Chemical Co.) as a fading retardant and studied with epifluorescence
microscopy using a narrow-band filter system for fluorescein
isothiocyanate (BX60, Olympus Optical Co., Tokyo,
Japan) or a confocal Zeiss LSM 410 (Carl Zeiss, Jana,
Germany).
RNA isolation and Northern blotting
Superficial and juxtamedullary cortex were cut out of the kidney
at 4 C and homogenized with a Disperser DIAX 600 in a denaturation
solution containing 4 M guanidium thiocyanate, 25
mM sodium citrate (pH 7.0), 0.5% sarcosyl, and 0.1
M 2-mercaptoethanol. RNA was extracted by the guanidium
thiocyanate-phenol acid-chloroform method, as described (10, 17).
Twenty micrograms of total RNA were denatured, electrophoresed in a
formaldehyde agarose gel, transferred onto Hybond N+ nylon
membranes (Amersham International) and UV cross-linked
(UVC 500, Hoefer Pharmacia Biotech Inc., San Francisco, CA).
Full-length complementary DNA (cDNA) probes of NaPi-2, NaSi-1,
ß-actin, and 18S ribosomic RNA were labeled with
[
-32P]-deoxycytidine triphosphate (3,000 Ci/mmol) by
random priming (RadPrime DNA Labeling System; Gibco BRL-Life Technologies, Grand Island, NY), and hybridization was carried
out at high stringency, as described (18). Signals were quantified by
image analysis with Gel Doc 1000 Video Gel Documentation System
(Bio-Rad Laboratories, Inc.) after exposure to x-ray films
(Hyperfilm MP).
Nuclear run-on
Cell nuclei were isolated from superficial and juxtamedullary
cortex, as described (19). Briefly, 0.5 g tissue was mixed with 5
ml lysis buffer (0.32 M sucrose, 5 mM
CaCl2, 3 mM magnesium acetate, 0.1
mM EDTA, 0.1% Triton X-100, 1 mM
dithiothreitol (DTT), 1 mM Tris-Cl, pH 8.0) and homogenized
in a loose-fitting pestle. After filtration through several layers of
cheesecloth, the filtrate was rehomogenized with 10 strokes in a
tightly fitting pestle. The homogenate was mixed with 1 vol 2
M sucrose solution (2 M sucrose, 3
mM magnesium acetate, 0.1 mM EDTA, 1
mM DTT, 10 mM Tris-Cl, pH 8.0) and centrifuged
over a cushion of the same solution at 30,000 x g for
45 min at 4 C. Nuclei were resuspended in glycerol storage buffer (40%
glycerol, 5 mM magnesium acetate, 0.1 mM EDTA,
5 mM DTT, 50 mM Tris-Cl, pH 8.0) at 100 x
106 nuclei/ml. Usually, about 30 million nuclei were
obtained per 0.5 g renal tissue. Labeling of nascent RNA
transcripts was performed exactly as described (19). A final
heterogeneous RNA probe of 8–10 x 106 cpm/2 ml
hybridization solution [10 mM
N-Tris[hydroxymethyl]methyl-2-aminoethanesulfonic
(TES; pH 7.4), 10 mM EDTA, 0.2% SDS, 300
mM NaCl] was incubated at 65 C for 36 h with single
nylon strips containing 5 µg of each denatured cDNA (NaPi-2, NaSi-1,
ß-actin, and linearized pBluescript as negative control) and 10 µg
18S, that were fixed by slot blotting and UV cross-linking. After
posthybridization washes and ribonuclease A treatment, nylon strips
were exposed to BioMax MS films and their corresponding intensifying
screens. Specific signals were quantified using the Gel Doc 1000 Video
Gel Documentation System (Bio-Rad Laboratories, Inc.).
Statistical analysis
All the data are expressed as mean ± SE. A
one-way ANOVA, with Fisher’s protected least-significant difference as
a multiple-comparison method, was used to compare data among groups and
was considered statistically significant at P <
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, together with phosphate and calcium
serum levels and the fractional excretion of phosphate. Plasma
concentration of phosphate was progressively increased by
T3 and reduced in hypothyroid animals that also showed the
highest fractional excretion of phosphorus.
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). Inward sodium-coupled phosphate
transport was increased by the hormone in a dose-dependent manner in
both superficial and juxtamedullary vesicles, although no significant
difference was observed between both hyperthyroid animals [those
receiving 2.5 (group D) and 5 (group E) µg T3/100 g
bw·day]. The stimulation of phosphate transport in juxtamedullary
BBM vesicles tended to be higher than the stimulation measured in BBM
vesicles from the superficial cortex; however, such differences were
not statistically significant.
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Thyroid hormone specifically increases NaPi-2 protein
To understand the effect of thyroid hormone on phosphate
reabsorption, we have analyzed the content of Na/phosphate
cotransporter in each of the treatments, by Western blotting assay,
using the same BBM vesicles as in the transport experiments. As
expected, we have found a correspondence between the changes in
transport activity elicited by the hormone and the changes in NaPi-2
protein. Fig. 2 shows the three
conditions analyzed: euthyroid, hypothyroid, and hyperthyroid animals.
These results indicate that chronically administered triiodothyronine
increased NaPi-2 transporter in a way similar to that of phosphate
transport, with more intensity in juxtamedullary than in superficial
renal cortex, although this difference was, again, statistically not
distinguishable. Whereas hypothyroidism reduced NaPi-2 protein to about
40% of euthyroid animals (60% reduction), hyperthyroidism increased
this protein 350%, compared with hypothyroidism; and 65%,
compared with euthyroidism. Signals corresponding to NaSi are shown as
unmodified controls.
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shows, hyperthyroidism elicited a
strong increase of NaPi-2 protein in the luminal membrane of proximal
tubules. This increase was also extended to the intracellular stores of
the transporter, shown in the figure as fluorescent-dotted
cytoplasm of the epithelial cells (2). Fig. 3 also shows ß-actin
filament labeling of tubular plasma membrane, which is not changed by
thyroid hormone.
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: In
parallel with the results of protein content, thyroid hormone induced
similar changes in specific NaPi-2 mRNA abundance in all conditions
assayed. In this case, the stimulation by T3 on
juxtamedullary NaPi-2 mRNA was also higher than in superficial cortex
mRNA (data not shown). As unmodified controls, RNA levels of
sodium-sulfate cotransporter, ß-actin, and ribosomic 18S are also
shown.
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, with comparison between hypothyroid
and hyperthyroid conditions: an approximately 2-fold stimulatory effect
of T3 in NPT-2 gene transcription was found
between these two conditions. However, an additional change in the
NaPi-2 mRNA stability in the rat cannot be excluded.
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). This decrease was
paralleled by a proportional reduction in phosphate transport capacity
by BBM vesicles from superficial and juxtamedullary proximal tubular
cells (Fig. 1). The effect of thyroid hormone to modulate
Na/Pi cotransport activity was less dramatic than in young
animals. Preliminary experiments with old rats, including group C,
showed (as expected) no differences with group A of the same age
animals. Therefore, this group was omitted when using old rats.
Instead, we always used group E to find a dose of T3
that resulted in effects similar to those seen in the young animals.
Chronic hypothyroidism elicited a 30% reduction in phosphate
reabsorption and plasma concentration, that was restored with thyroid
hormone treatment, whereas chronic hyperthyroidism increased phosphate
transport by only 20% over control levels and 50% over the
hypothyroid status, even when plasma concentration of the hormone was
more than 10 times the physiological levels. Interestingly, these
thyrotoxic doses of T3 in aged rats were still not able to
restore the basal level of phosphate transport present in control young
animals (Figs. 1 and 6), although
additional factors (different from a reduced sensitivity to
T3) may be responsible for the blunted stimulatory effect
of this hormone.
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). Densitometric analysis revealed a
40% reduction of NaPi-2 protein in hypothyroid, compared with
euthyroid animals, whereas hyperthyroidism increased NaPi-2 protein
110%, with respect to hypothyroidism, and 40% over euthyroid animals.
Similar results were obtained for the specific NaPi-2 mRNA content, by
Northern blotting, in both superficial and juxtamedullary kidney cortex
(Fig. 4), that was also caused by an increase in transcription of the
NPT-2 gene, although this increase was less effective than
in young animals (Fig. 5).
Figure 6 summarizes the influence of aging on the T3
stimulatory effect on phosphate transport rate, NaPi-2 protein, and
mRNA contents, and it compares young-control nonoperated animals with
old-control and old-hyperthroid TPTX-animals. On the one hand,
transport rate and NaPi-2 protein and RNA contents were less than half
in control (nonoperated) old animals, compared with control young rats.
On the other hand, hyperthyroidism in old rats increased NaPi-2 RNA
content above the level in young animals. However, protein content was
similar in hyperthyroid old animals and euthyroid young animals, and in
terms of phosphate transport rate, these old animals exhibited even
less transport rate per protein unit than the young rats. Therefore,
these results seem to indicate that the aging process affects all the
steps of the stimulatory effect of thyroid hormone on the cell
physiology of phosphate transport, from gene transcription to protein
function.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) to a level that is able to increase serum
Pi concentration (Table 1). Higher (pharmacological) doses
of T3 further increase Pi renal reabsorption
and serum phosphate level. This effect is mediated by parallel
increases in the amount of Na/Pi cotransporter (NaPi-2) in
the brush border of proximal tubular epithelial cells (Figs. 2 and 3).
The specific increase in protein content is, in turn, caused by an
increase in the intracellular content of the specific NaPi-2 mRNA (Fig. 4), which was produced by stimulation of the transcription rate of the
corresponding gene, NPT-2 (Fig. 5). These results
point to the classic mechanism of thyroid hormone, acting through
intracellular receptors and binding to thyroid hormone response
elements (TREs) in the corresponding gene promoters (20). However, in
spite of the recent identification and sequence of several type II
(NaPi-2, NPT-2) gene promoters (21), no consensus sequence
of classic TREs has been found, but only a putative vitamin D-response
element (22). Therefore, the stimulatory effect on
NaPi-2-mediated transport could be explained by the existence of a
novel TRE in the NPT-2 gene or by an indirect T3
stimulation; i.e. T3 could stimulate the
synthesis of a protein responsible for a direct effect on the
NPT-2 gene. Future experiments, using these gene promoters,
should clarify this question. To our knowledge, our study is the first that clearly shows a physiological role for T3 on renal tubular phosphate reabsorption: chronic hypothyroidism induces a substantial decrease in serum phosphate, as well as an inhibition of phosphate transport, that is reversed by the exogenous physiological treatment with T3. It is interesting that the reduction in phosphatemia occurs in spite of the existence of alternative mechanisms for increasing phosphate reabsorption in the rat (e.g. acute and chronic adaptation to dietary phosphate deprivation, and others), because none of them is able to restore the euthyroid level of serum phosphate in hypothyroid animals. This could be explained as either the existence of additive effects of all these regulatory mechanisms, T3 being a major regulator, and/or as the need of thyroid hormone presence for a correct functioning of all other additional mechanisms. The second possibility is more likely to occur because, as it has been shown, euthyroid rats, chronically fed with low (0.1% Pi) phosphate diet vs. control (0.6% Pi) or high (1.2% Pi) phosphate diets, are able to maintain a normal phosphatemia, thanks to an avid renal adaptive mechanism that induces an increase of almost 100% reabsorption of phosphate ultrafiltrate (18, 23). In this case, the adaptation consists in both increases in specific NaPi-2 mRNA and protein content in tubular cells, although this effect is not mediated by NPT-2 gene transcription stimulation but by an increase of NaPi-2 mRNA stability (24, 25). In addition, though the expected transient hypophosphatemia caused by dietary phosphate deprivation induces the mentioned increase in NaPi-2 mRNA and protein, in the case of hypothyroidism, the effect is just the contrary (that is, reduction in NaPi-2 mRNA and protein content).
From these results, we can initially conclude that thyroid hormone is a major controller of phosphate homeostasis in long-term regulation, which should be distinguished from acute regulation, a less frequent physiological condition. This conclusion is also supported by a characteristic of our experimental design: to avoid interferences with PTH, the animals were made TPTX, instead of just thyroidectomized. Therefore, our animals possessed hypothyroid and hypoparathyroid status. As it has been recently shown, hypoparathyroidism induces an increase in phosphate reabsorption through lack of the phosphaturic hormone (26). Therefore, when the animals have normal levels of PTH in serum, the actual effect of chronic hypothyroidism is, most likely, more dramatic than we have shown in the present paper.
With respect to the stimulatory effect of T3, treatment
with T3 (5 and 10 times the physiological dose) further
increased Pi reabsorption through the same mechanisms as
the physiological dose (RNA and protein synthesis). The stimulatory
effect of chronic hyperthyroidism was already saturated at 5 times the
physiological dose in young animals (see Fig. 1) and was similar to the
increase obtained with acute thyrotoxic doses, 400 times the
physiological dose (200 µg T3/100 µg BW·12 h, for 3
days) shown in previous papers and in our own lab (Refs. 4, 23 ; data
not shown). The equivalence of our chronic hyperthyroid doses to acute
thyrotoxic doses (because of saturability) shown in the present study,
with respect to the stimulation of phosphate reabsorption, could make
feasible the use of low-dose thyroid hormone as a long-term therapy in
several disorders involving phosphate homeostasis unbalance or bone
diseases.
Previous works (4) reported that the main effect of T3 takes place on the renal juxtamedullary cortex (mostly straight tubules), in spite of the higher transport rate and NaPi-2 mRNA and protein content of the superficial cortex (mostly convoluted tubules; Ref. 15). In the present paper, we have not found such difference in T3 effect; that again, could be caused by the differences in the experimental design: long-term physiological T3 doses vs. acute thyrotoxic doses in the previous work.
Finally, two comments must be made with respect to the two controls used, the NaSi and ß-actin. Two groups have found discrepancies, in relation to the the effect of T3 on sulfate transport in BBM vesicles: no effect in rat (4, 5); and stimulation in mouse (27). Our results have shown a lack of T3 effect on transcription and RNA and protein content of the NaSi transporter. With respect to ß-actin, it has been shown recently that thyroid hormone induces a 2-times inhibition in its mRNA levels in skeletal and white muscle tissue (28). In the present work, we have also not found any effect on mRNA or protein ß-actin levels. This difference could be explained by tissue-specific effects, but also by the differences in both experimental design and the dose: 0.5 µg T3/100 µg BW vs. 100 µg/100 µg BW in the previous paper.
Effect of aging on thyroid hormone action
There are two main results of the present study in relation to the
effect of aging: first, NPT-2 gene transcriptional activity
is decreased with the age of the animals; and second, the stimulatory
effect of thyroid hormone is also reduced in the aging. In a previous
paper (10), we have published that old rats contain less NaPi-2 mRNA
and protein per tissue unit than young rats. Now, we have shown that
such decrease may be caused by a reduced transcription rate of the
corresponding gene, which might explain the lower serum phosphate
concentration in old animals. Such a decrease is a general
characteristic of the aging process in mammals (29). Old rats are also
less sensitive to T3 than the young ones, and this can be
observed in both hypothyroid and hyperthyroid animals. On the one hand,
old hypothyroid animals show a smaller reduction in phosphatemia than
young hypothyroid animals (in comparison with the respective euthyroid
rats), as well as proportional (smaller) alterations in transport rate,
protein, and mRNA levels of the renal phosphate transporter NaPi-2. On
the other hand, the stimulatory effect of T3 to induce
hyperthyroidism is also less effective in old than in young animals,
for all parameters analyzed.
In addition, the reduction in the basal transcriptional rate of NaPi-2
mRNA in aged rats is not caused by an age-dependent reduction in serum
levels of T3. It should be noted that some authors have
reported a decrease in serum T3 levels with age in humans
(30), caused by both decreases in pituitary TSH release and peripheral
degradation of T4 that, in return, result in a decline in
serum and tissue concentration of T3 (31). Our results are,
however, in agreement with other studies (e.g. Ref. 32),
which have not found differences in serum T3 concentrations
between young and old rats, and they suggest that the relative
hypothyroid status of the aging rat is not produced by a decreased
concentration of T3 but is caused by a reduced relative
response to the hormone. In fact, the effect of the aging can be
detected in all the cellular and molecular processes of phosphate
transport regulation: transcription, translation, and function of the
NaPi-2 protein (Fig. 6).
In summary, we have shown a physiological role of T3 in the regulation of, mainly, basal level of renal phosphate reabsorption, which is impaired with aging. Furthermore, our study is the first that shows genomic regulation of the corresponding gene, NPT-2, by thyroid hormone and the aging process.
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Acknowledgments |
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Footnotes |
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Received September 9, 1998.
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