1 Department of Biological Sciences, University of Delaware, Newark, Delaware 19716; and 2 Department of Physiology, University of Iceland, IS-101 Reykjavík, Iceland
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ABSTRACT |
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The
electrophysiological effects of parathyroid hormone (PTH) were studied
in a primary cell culture model of the chick (Gallus domesticus) proximal tubule. In this model, confluent monolayers are grown on permeable filters and exhibit vectorial transport, including glucose-stimulated current. Under short-circuit conditions, PTH, at 109 M, induced a positive current [short-circuit
current (Isc)] response, with an average 2-min
peak response of 14.30 ± 1.58 µA/cm2 over the
baseline Isc, followed by a slow decay. The PTH
response was dose dependent, with a half-maximal response at 5 × 10
9 M and maximal response at 5 × 10
8
M. Forskolin and dibutyryl-cAMP also stimulated
Isc, as did the phosphodiesterase inhibitor
IBMX. In contrast, the phorbol ester PMA inhibited baseline
Isc. The PTH response was nearly abolished by
apical addition of 100 µM EIPA, an inhibitor of
Na+/H+ exchangers, and partially blocked by the
Cl
channel blockers
5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 100 µM) and
glibenclamide (300 µM). Higher doses of EIPA or NPPB alone (500 µM)
were almost fully effective, with no or slight additional effects of
NPPB or EIPA, respectively. The anion exchange inhibitor DIDS (100 µM) and the Na+ channel blocker amiloride (10 µM) had
no effect. Bilateral reduction of Cl
in the buffer, from
137 to 2.6 mM, abolished the PTH response; increasing Cl
concentration restored the Isc response, with a
half-maximal effect at 50 mM. These data suggest that, in the chick
proximal tubule, PTH activates both an Na+/H+
exchanger and a Cl
channel that may be functionally linked.
avian kidney; short-circuit current; chloride channels; cystic fibrosis transmembrane regulator; glibenclamide
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INTRODUCTION |
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PARATHYROID HORMONE (PTH) is known to affect a number of proximal tubule (PT) transport systems. In rats, rabbits, and other mammalian species, PTH inhibits Na+, fluid, and bicarbonate reabsorption in vivo and in vitro (2, 4, 16, 29; for a review, see Ref. 15). A major part of this effect is linked to inhibition of an apical Na+/H+ exchanger (NHE) isoform, identified as NHE3 (10, 14, 16, 54). On the basis of recovery of intracellular pH from an imposed ammonium chloride acid load, PTH treatment inhibits an amiloride- and EIPA-sensitive exchanger in both native tissues and in the proximal-like opossum kidney (OK) cell line (10, 17, 40). Furthermore, studies with brush-border membrane vesicles (BBMV) have shown that PTH treatment reduces the activity of pH gradient-driven 22Na uptake (14, 16, 20). PTH was also shown to decrease the Vmax for 22Na uptake by OK cells (30). These findings are suggestive of a PTH-induced decrease in transporter number. In support of this, more recent immunoblotting studies and subcellular fractionation experiments have shown a PTH-induced internalization of NHE3 from the apical membrane to a subapical, intracellular compartment (10, 14, 16, 18, 54). PTH also reduces NHE3 activity via phosphorylation of cytoplasmic domains of the transporter, thus indicating a dual mechanism of regulation (10, 14). These effects of PTH appear to be mediated largely via the cAMP-dependent protein kinase (PKA) signaling pathway (1, 10, 17, 20, 29, 40). Similarly, PTH also inhibits an apical sodium phosphate (Pi) cotransport system, resulting in increased urinary excretion of Pi (17, 54).
There is much less known about PTH function in the avian PT. There is some evidence for an apical NHE in chickens (35), and PTH in vivo leads to increased whole animal urinary flow rates, Na+ excretion, and urinary pH, suggesting PTH inhibition of this system (26). However, this has not been demonstrated directly. Moreover, there are a number of known differences in proximal transport characteristics between birds and mammals. For example, we previously demonstrated that superficial PTs of the European starling do not acidify the urine (24); i.e., there was no measurable pH gradient between the tubule lumen and peritubular blood and therefore no preferential bicarbonate reabsorption, as seen in mammalian PTs (15). We and others were also unable to detect, by histochemical methods, PT carbonic anhydrase activity, whereas distal tubule and collecting duct segments were clearly positive (25, 37). Martinez et al. (28) found that superficial, nonlooped nephrons of chickens seem to possess none of the known mammalian basolateral acid-base transporters.
The avian PT also possesses specific systems for secretory transport (basolateral to apical) of both urate and Pi, although there is little known about these systems (3, 7, 13, 36, 52). Such secretory processes may have evolved in part to compensate for the lower filtration rates found in nonmammalian nephrons (7, 36). Thus PTH in birds is thought to increase Pi excretion by both inhibition of a reabsorptive flux, as in mammals, and by stimulation of a secretory flux (13, 36, 52).
We have recently developed a primary cell culture model of the avian
(chick) PT using methods similar to those developed for rabbit and rat
(45). Cells grown as confluent monolayers on permeable
membrane filters become highly polarized and exhibit transepithelial
transport, measurable by classic electrophysiological methods. Using
this approach, we undertook these studies to investigate PTH effects on
the avian PT. The results demonstrate a novel effect of PTH on this
system involving stimulation of a Cl-dependent and
EIPA-sensitive short-circuit current (Isc).
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MATERIALS AND METHODS |
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Reagents and supplies. The growth media and supplements, collagen, Percoll, PTH [bovine PTH-(1-34) fragment], and all other agonists and antagonists used in this study were obtained from Sigma (St. Louis, MO). Dispase and collagenase were from Roche Molecular Biochemicals (Indianapolis, IN). The membrane filters used were Nunc (Naperville, IL) 10-mm tissue culture inserts with an 0.02-µm Anopore membrane. Inhibitors and agonists were prepared as 1,000× stock solutions in DMSO or water.
Cell culture. Chick PT cultures were prepared as described previously (45), using methods similar to those for mammalian primary cultures (12, 19, 48). Briefly, 4- to 7-day-old White Leghorn chicks were killed by cervical dislocation (approved by the International Animal Care and Use Committee), and kidney tissue was removed asceptically. Pieces of tissue were pooled from five to seven chicks in ice-cold Hanks' balanced salt solution (HBSS) with penicillin and streptomycin. The pooled tissue was then minced and enzymatically disaggregated in a solution containing 1 mg/ml collagenase A and 0.6 U/ml Dispase for 30 min at 37°C. This digested material was then triturated with a 10-ml pipette and sieved through a stainless steel screen (30 mesh, 0.52-mm openings). The filtrate, at this point, consisted of short, intact tubule fragments of ~100-200 µm in length. Following the techniques described for isolation of rat PTs (48), the tubule suspension was washed multiple times in HBSS by low-speed centrifugation and then placed in a 1:1 mixture of Percoll and 2× Krebs-Henseleit buffer containing (in mM) 240 NaCl, 8 KCl, 2 KH2PO4, 30 NaHCO3, 2.4 CaCl2 · 2H2O, 2.4 MgSO4 · 7H2O, 10 glucose, and 20 HEPES.
The suspension was centrifuged through the Percoll density gradient at 15,000 g for 30 min (4°C). For chick kidney, this process resulted in two major tissue bands at low and high densities. The high-density band, designated as the "PT band," consisted almost entirely of short PT fragments, as assessed by microscopic appearance and marker enzyme enrichment (45). The PT band was removed from the Percoll and washed several times in HBSS and one time in growth media. These washing steps and all subsequent work was done in the absence of antibiotics. A final suspension of tubules was prepared in 3-4 ml of growth media and used for seeding culture inserts. Before each preparation (1 day), 12 Nunc tissue culture inserts were collagen coated by soaking the filters in a 20:1 dilution of type I calfskin collagen, removing excess solution and allowing the filters to completely air-dry. The inserts were prewetted with growth medium several hours before seeding. The growth media used was serum-free and antibiotic-free DME/F-12 (1:1) supplemented with 5 µg/ml insulin, 5 µg/ml transferrin, 5 ng/ml selenite, 5 × 10Electrophysiology.
Filter inserts with intact monolayers were mounted in modified
Ussing chambers with adapters fitted for the Nunc 10-mm cups (Warner
Instrument, Hamden, CT). An "O" ring sealed the outside of the cup
within the adapter. Thus the epithelial monolayer formed an intact
barrier between circulating apical and basolateral Ringer solutions,
with no edge damage. A transport buffer containing (in mM) 130 NaCl, 4 KCl, 1.3 CaCl2, 1 MgSO4, 5 HEPES, and 25 NaHCO3 was circulated on both sides and gassed with 5%
CO2-95% O2 (pH 7.5). For Cl
substitution experiments, NaCl and KCl were partially or completely replaced with gluconate salts on both sides. Heated reservoirs kept the
buffers (16 ml on each side) at 37°C. The monolayers were
short-circuited with an automatic two-channel voltage clamp (DVC 1000;
WPI) with correction for fluid resistance compensation. Ringer-agar
bridges were used to electrically couple the apical and basolateral
solutions to a matched pair of calomel half-cells for measurement of
the potential difference (PD). A second set of bridges was connected to
a pair of Ag/AgCl wires for passing current. Isc
was measured continuously and displayed on a strip-chart recorder, with
intermittent measurement of the open-circuit PD. Transepithelial
resistance (TER) was also monitored continuously by current deflections
in response to 2-s changes in the clamping voltage (to 1 mV) every 5 min.
Immunoblotting. Standard Western blotting methods were used to investigate the possible presence of a CFTR-like protein in PT culture extracts. Monolayers were extracted in 1% Nonidet P-40 containing a protease inhibitor cocktail (Complete Mini; Roche Molecular Biochemicals). Total protein (30 µg) was loaded on 8% SDS-polyacrylamide gels and probed with the following two separate commercial anti-human CFTR antibodies: a COOH-terminal monoclonal MAB 25031 (R & D Systems, Minneapolis, MN) and monoclonal MA1-935 (Affinity Bioreagents, Golden, CO). Neither antibody detected specific CFTR antigen in these extracts.
Data analysis and statistics.
Data are expressed as means ± SE. The responses to PTH,
forskolin, DBcAMP, and PMA were analyzed by measuring the changes in
current at 2, 10, and 20 min after addition. Effects of PTH in the
presence or absence of inhibitors were analyzed at 2 and 10 min after
hormone addition. Two-minute peak responses to PTH were used for the
PTH dose-response and Cl substitution series. Significant
differences between groups (P < 0.05) were assessed
with ANOVA followed by a Tukey test or with paired and unpaired
Student's t-tests.
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RESULTS |
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Baseline electrophysiological characteristics.
Table 1 presents baseline
electrophysiological measurements and Isc
responses to glucose addition for all groups used in this study.
Baseline Isc was somewhat variable, ranging from
mean values of 7 to 15 µA/cm2, but with no statistically
significant differences among groups. All monolayers grown under these
conditions and tested with normal Cl transport buffer
consistently displayed low PDs and a modest TER, ranging from 0.6 to
1.9 mV and 63 to 150
· cm2,
respectively. There were some significant differences in TER among
groups in Table 1, mostly compared with the higher TER seen in the
monolayers tested at the lowest Cl
concentrations
([Cl
]; 2.6 mM). All monolayers also consistently
displayed a glucose-stimulated increment in Isc,
attributable to a Na+-glucose luminal cotransporter and
characteristic of the vertebrate PT (13, 15, 45).
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PTH-induced current response.
Figure 1 presents tracings from two
examples of experiments on paired PT monolayers. As seen in Fig.
1A, top trace, exposure of the chick monolayers
to 1.0 × 109 M PTH resulted in a positive current
response that peaked at 2 min and slowly decayed thereafter. Data from
43 PTH-treated monolayers (taken from the control monolayers from all
antagonist groups combined) are summarized in Fig.
2. The peak response at 2 min averaged
14.30 ± 1.58 µA/cm2, falling thereafter to
6.78 ± 0.63 and 3.38 ± 0.44 µA/cm2 at 10 and
20 min, respectively, still significantly different from the baseline
current (P < 0.01).
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Effects of transporter and channel blockers on the PTH-stimulated
Isc.
A number of transport inhibitors were found to partially block the
postglucose Isc, as exemplified by EIPA, an
inhibitor of NHEs (Fig. 1A, bottom trace). Table
2 summarizes the initial effects of these
inhibitors on post-glucose Isc and TER values. The NHE inhibitor EIPA, the Cl channel blockers
glibenclamide and NPPB, and the Na+ channel blocker
amiloride all significantly reduced Isc, with EIPA causing the greatest effect. DIDS, a blocker of
Cl
/base exchange, had no overall effect on
Isc, although some of the individual monolayers
showed either increases or decreases in current. EIPA, glibenclamide,
and NPPB also significantly increased TER, as did DIDS. Amiloride,
however, had no significant effect on this parameter.
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Dependence of the PTH response on
[Cl].
The PTH-induced Isc response was found to be
completely dependent on the presence of Cl
(Fig.
5). Symmetrical reduction of
[Cl
] in the bathing solutions to 2.6 mM essentially
abolished the PTH response. Increments in [Cl
] between
25 and 137 mM restored the PTH response in a dose-dependent manner.
Half-maximal stimulation was obtained at [Cl
] levels of
50 mM and maximal stimulation at levels >65 mM.
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DISCUSSION |
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This study describes a novel effect of PTH on a chick PT culture
system. This primary culture model has previously been shown to exhibit
properties characteristic of vertebrate PTs, including apical
microvilli and vectorial transport, exemplified by glucose-stimulated Isc (45). In the present study, PTH
at 109 M consistently induced a positive increase in
Isc that was EIPA sensitive. The
Isc response peaked at 2 min and then decayed
over a 10- to 20-min time course, possibly reflecting receptor
desensitization (Figs. 1A and 2). The
Isc response was dose dependent over a 100-fold range, with a half-maximal effect at 5 × 10
9 M PTH.
This dose-response relationship is similar to that seen for PTH
inhibition of fluid reabsorption in vivo (4) and for stimulation of cAMP production (9) and inhibition of NHE
activity (17) in the OK PT cell line. The lack of response
to even high doses of the avian antidiuretic hormone arginine vasotocin
indicates specificity of this PTH response in these chick PT cells.
Forskolin resulted in a similar Isc response to PTH. The large 2-min overshoot appeared to be because of secondary phosphodiesterase activation, since separate experiments with IBMX and 10-fold lower forskolin maximally stimulated Isc without an overshoot (see RESULTS). The sustained current after forskolin showed little decay with time. The membrane-permeant cAMP analog DBcAMP also increased Isc, but with a slower onset and lack of overshoot (Figs. 1B and 2). These observations suggest that PTH is acting on this transport system via the adenlylate cyclase/PKA signaling pathway. Interestingly, the phorbol ester PMA, an activator of PKC, caused a decrease in baseline Isc. Thus these two signaling pathways, both of which are activated by PTH in proximal cells (1, 9), appear to have opposite effects on this Isc response. In the OK cell model, it has generally been observed that activation of either the PKA or PKC signaling pathways inhibits NHE activity (1, 17). On the other hand, PKC stimulation resulted in increased Na+/H+ activity in both native tissues (rabbit BBMV) and primary cultures of rabbit PTs (19, 51). Thus the potential role of PKC regulation of apical NHE activity is uncertain but may be related to different PKC isoforms present in various cell types or under different assay conditions (15).
In the mammalian PT, PTH is known to inhibit Na+, fluid,
and bicarbonate reabsorption, largely through its inhibition of the NHE3 isoform of the NHE family (10, 14, 16, 54). However, in this chick primary culture model, PTH appears to stimulate an NHE
activity that is either linked to or dependent on a Cl
transport process. Several observations support this conclusion. First,
the Isc response to PTH was nearly abolished by
apical addition of 100 µM EIPA (Figs. 1A and 4). This
amiloride analog is generally considered to be a selective inhibitor of
NHE transporters, although various isoforms may have different
inhibitory constants (18, 34). In contrast, amiloride
itself, at a dose that inhibits electrogenic epithelial Na+
channel activity (32, 53), had no effect on the
PTH-induced current response, although it did slightly decrease the
baseline Isc (Table 2 and Fig. 4). Thus it seems
unlikely that PTH upregulates Na+ channels in this system,
as has been proposed for mammalian PTs (15).
Second, regarding Cl dependency, both Cl
replacement and two different Cl
channel blockers
significantly inhibited the PTH-induced response. Glibenclamide, a
sulfonylurea receptor inhibitor used to stimulate
-cell insulin
release, has also been widely used as a blocker of CFTR
Cl
channels (41, 43). Similarly, the
arylaminobenzoate NPPB is known as a potent inhibitor of a variety of
Cl
channels (33, 38, 41). Both of these
blockers, when added to the apical side, significantly reduced the
PTH-induced Isc response (Fig. 4). In contrast,
apical addition of 100 µM DIDS has no significant effect on this PTH
response. DIDS is primarily used at these concentrations as a blocker
of Cl
/base or Cl
/formate/oxalate exchangers
of the PT (49). This compound also blocks some types of
Cl
channels, although typically at higher concentrations
(32-34, 38, 41). However, it is ineffective against
CFTR channels from the extracellular side (41). Thus this
result also rules out such anion exchangers as a possible mechanism
behind the PTH-induced current response. It should be noted that, when
used at higher concentrations, both NPPB and EIPA eliminated
~80-90% of the total stimulated current, and there was almost
no additivity of these two blockers (see
RESULTS).
Bilateral reduction of [Cl] in the bathing solutions,
from 137 to 2.6 mM, essentially abolished the
Isc response (Fig. 5). Increasing
[Cl
] over the range of 25-137 mM restored the full
hormone response, with a half-maximal response at 50 mM. These data
suggest that a low-affinity Cl
transport process is
somehow linked to the PTH response. Because, in the present study, we
did not measure isotope fluxes, it is not possible to identify the
ion(s) responsible for the Isc response. Given
the simple composition of the transport buffer used in these studies,
positive currents would most likely be mediated by Cl
secretion (basolateral-to-apical flux), Na+ reabsorption,
or some combination of these. A number of studies have suggested that
intracellular Cl
levels in PT cells lie above
electrochemical equilibrium; i.e., increased apical Cl
conductance would result in Cl
exit from the cell, rather
than entry (44). It should also be noted that, under these
short-circuit conditions, passive (i.e., electrically driven) coupling
of Cl
fluxes is eliminated. Thus, taken together, these
data suggest that PTH activates both NHE activity and a
Cl
channel, one that is possibly CFTR related. These
activities appear to be functionally linked, either at the transport
level or via a common regulatory pathway.
Previous clearance studies in chickens have shown that, as in mammals, PTH administration results in whole animal diuresis, natriuresis, and urinary alkalinization (26), suggesting a conventional inhibitory action of PTH on NHE3 activity of the PT, in addition to the stimulated system seen in this study. This leads to the question of whether a PTH-induced Isc response may also be present in mammalian PTs, masked by the much larger inhibitory effect on Na+ reabsorption. To our knowledge, there are no other reports of PTH-stimulated current in PT cells. However, several observations suggest that a similar system may be present in mammals. First, in primary cultures of human PT cells, forskolin caused a similar positive Isc response to that seen in the chick cultures (47). PTH was not tested in these human cells, however, and possible implications of the forskolin response were not addressed.
Second, patch-clamp studies in primary cultures of rabbit PTs revealed
a PTH-activated Cl channel (46). This
Cl
conductance could also be activated by forskolin, by a
catalytic subunit of PKA, and, interestingly, also by PKC exposure.
cAMP- and PKA-activated Cl
channels were also observed in
primary cultures of rat PTs (12). Furthermore, PTH and
cAMP have been shown to increase Cl
membrane permeability
in rat kidney BBMV (27).
Regarding the possibility of CFTR localization to the PT, several studies have demonstrated CFTR mRNA in PT segments or in cultured cells (21, 31, 38), whereas expression at the protein level has been observed by some (6, 11), but not other, investigators (38). In the present study, attempts were made to detect CFTR protein in monolayer extracts using two different anti-human CFTR antibodies. Although these attempts were unsuccessful, this could indicate that the antibodies lacked sensitivity or that the transporter activity is species specific or distinct from the human CFTR protein, despite pharmacological similarities. Nevertheless, the recent realization that CFTR controls a wide variety of membrane channels and transporters (22, 42) and that a family of intracellular signal complex proteins, known as Na+-H+ exchanger regulatory factors (NHERFs), bind both NHE and CFTR via PDZ domains (50) provides a possible model for linkage of NHE and CFTR function.
Although the transport mechanism behind the PTH-induced
Isc response is unknown, an intriguing
possibility is suggested by recent studies of a novel
Cl-dependent NHE found in rat distal colon crypt cells
(33, 34, 39). As determined by pH gradient-stimulated
22Na uptake by apical membrane vesicles, this "Cl-NHE"
requires Cl
and is sensitive to both NPPB and EIPA. High,
channel-blocking concentrations of DIDS also inhibited activity, but
lower concentrations, used to inhibit anion exchangers, had no effect
(33, 34). Moreover, an antibody to CFTR also partially
blocked Cl-NHE activity (33). Recently, this transporter
was cloned from rat distal colon crypt cells and shown to have homology
with NHE1, but with a markedly shortened and novel COOH-terminal domain
(39). Of particular interest, cDNA probes for this
transporter revealed widespread distribution of specific mRNA in
several rat tissues, including kidney. This again raises the
possibility of a system similar to that described in the present study
in mammalian PTs. In this regard, Choi et al. (8) have
shown that 50% of EIPA-sensitive proximal NHE activity remains intact
in NHE2 plus NHE3 double-knockout mice, suggesting the presence of an
as yet undefined NHE activity.
It is unclear what physiological function this system might have in the
avian and/or mammalian PT or how its activation by PTH fits in with the
other known effects of this hormone. Because these studies were
performed in a tissue culture environment, in vivo implications need to
be considered with caution. Among other factors, hormone release
patterns (pulsatile vs. continuous), stability, and concentration in
the whole animal will be different. Furthermore, it is possible that
the observed current response represents only one manifestation of a
multistep process in vivo. Nevertheless, it is interesting to consider
several avian PT transport systems that are affected by PTH. In birds,
PTH is known to stimulate a secretory component of Pi
transport (52) in addition to its inhibition of
reabsorptive transport (13, 36). PTH was also shown to
increase urate clearance in birds, although the mechanism of this
response was not determined (23). It is also of interest that Cl secretion has been correlated with net fluid
secretion in vertebrate PTs, clearly demonstrated in teleosts
(5) and hypothesized to exist in other vertebrates
(44). Potential interactions among these transport systems
deserve further study.
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ACKNOWLEDGEMENTS |
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This study was funded by National Science Foundation Grant IBN-9870810 (G. Laverty). Additional support was from The Icelandic Research Council and the University of Iceland's Sattmalasjodur (S. S. Árnason). Funding was also provided (A. Sheldon) by a grant from the Howard Hughes Medical Institute to the University of Delaware (Improving Undergraduate Biology Education).
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. Laverty, Dept. of Biological Sciences, Univ. of Delaware, Newark, DE 19716 (E-mail: Laverty{at}udel.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 27, 2002;10.1152/ajprenal.00281.2002
Received 6 August 2002; accepted in final form 15 December 2002.
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