1 Nephrology Research and Training Center, Division of Nephrology, and 2 Division of Hematology and Oncology, Department of Medicine and Physiology, and Gregory Flaming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294; and 3 Membrane Transport Research Group, University of Montreal, Montreal, Quebec, Canada H3C 3J7
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ABSTRACT |
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Na-K-ATPase is the nearly ubiquitous enzyme that maintains low-Na+, high-K+ concentrations in cells by actively extruding Na+ in exchange for K+. The prevailing paradigm in polarized absorbing epithelial cells, including renal nephron segments and intestine, has been that Na-K-ATPase is restricted to the basolateral membrane domain, where it plays a prominent role in Na+ absorption. We have found, however, that macula densa (MD) cells lack functionally and immunologically detectable amounts of Na-K-ATPase protein. In fact, these cells appear to regulate their cytosolic [Na+] via another member of the P-type ATPase family, the colonic form of H-K-ATPase, which is located at the apical membrane in these cells. We now report that this constitutively expressed apical MD colonic H-K-ATPase can function as a Na(H)-K-ATPase and regulate cytosolic [Na+] in a novel manner. This apical Na+-recycling mechanism may be important as part of the sensor function of MD cells and represents a new paradigm in cell [Na+] regulation.
macula densa; sodium-potassium-5'-adenosinetriphosphatase; colonic hydrogen-potassium-5'-adenosinetriphosphatase; sodium-binding benzofuran isophthalate
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INTRODUCTION |
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OVER THE LAST FEW YEARS, DIFFERENT members of the Na-K/H-K-ATPase gene family have been identified and localized in various epithelia within the kidney (10, 12, 25). There is a high abundance of Na-K-ATPase along the basolateral membrane of various nephron segments (11), with the highest activity occurring in the outer medulla (thick ascending limb; TAL). Na-K-ATPase is involved in the development and maintenance of transmembrane Na-K electrochemical gradients that, in epithelial cells, are necessary for Na+ reabsorption and K+ secretion. In terms of the two other subgroups of this ATPase family, different isoforms of both the gastric H-K-ATPase and the colonic (nongastric) H-K-ATPase exist in the kidney (12, 25) and are located mainly in the distal nephron. Presently, it is thought that these ATPases play a role in K+ absorption and urinary acidification.
It has been thought that Na-K-ATPase activity and, consequently, the
capacity for transepithelial NaCl transport are relatively low in
macula densa (MD) cells, at least compared with the adjacent cortical
TAL (cTAL). This was based, in part, on previous work (21)
that demonstrated very low Na-K-ATPase activity in MD cells. This
finding is intriguing, because these cells are located at the end of
cTAL and act as sensor cells, detecting changes in luminal NaCl
concentration ([NaCl]L) and sending signals to
the mesangial-afferent arteriolar complex (tubuloglomerular feedback; TGF) (20). MD cell signaling has been shown to involve
apical NaCl transport mechanisms, including a furosemide-sensitive
Na+-2Cl-K+ cotransporter
(3, 19). Also, the type 2 Na+/H+
exchanger isoform (NHE2), another Na+-entry pathway, is
located at the apical membrane of MD and cTAL cells (15).
It has been suggested that transport-induced secondary changes in
intracellular [NaCl] are critically important in MD cell signaling.
This controversy, i.e., importance but scarcity of NaCl transport,
suggests a unique way of Na+ handling in MD cells.
Therefore, the purpose of these studies was to measure
transport-related changes in MD intracellular [Na+]
([Na+]i). For comparison, similar transport
measurements were obtained in adjacent cTAL cells. These studies
demonstrate that MD cells possess an apical H(Na)-K-ATPase that may be
the primary Na+-efflux pathway for these cells. Similarity
in pharmacological profiles of the MD and distal colon H-K-ATPases
indicates that MD cells express a form of the colonic H-K-ATPase.
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MATERIALS AND METHODS |
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Tubule and colonic crypt preparation. We isolated and perfused cTALs with attached glomeruli dissected from kidneys of rabbits kept on a standard diet [15% rabbit diet (W) 8630, Teklad, Madison, WI] as described earlier (14, 15). This preparation contains the otherwise inaccessible MD cells and allowed us to manipulate the composition of the tubular fluid at the apical side (perfusate) independently from the basolateral interstitium (bath). The dissection solution was a modified Ringer solution composed of (in mM) 25 NaCl, 5 KCl, 1 MgSO4, 1.6 Na2HPO4, 0.4 NaH2PO4, 1.5 CaCl2, 5 D-glucose, 5 HEPES, and 125 N-methyl-D-glucamine-cyclamate and adjusted to a pH of 7.4. Tubules were cannulated and perfused with this same Ringer solution. The preparation was bathed in 150 mM [NaCl] Ringer solution continuously aerated with 100% O2 and exchanged at a rate of 1 ml/min. Temperature was maintained at 37oC. Individual crypts of the distal colon from rabbit were also hand-dissected and perfused with methods similar to those used in perfusing kidney tubules.
[Na+]i measurement. [Na+]i of MD, cTAL cells, and the upper third of colonic crypt epithelial cells, known to express the H-K-ATPase (18), was measured with dual-excitation wavelength fluorescence microscopy (Photon Technologies, Princeton, NJ) by using the fluorescent probe sodium-binding benzofuran isophthalate (SBFI; Teflabs, Austin, TX) with techniques similar to those described for Ca2+ and intracellular pH (pHi) measurements (14, 15). SBFI fluorescence was measured at an emission wavelength of 510 nm in response to excitation wavelengths of 340 and 380 nm, alternated at a rate of 25 Hz by a computer-controlled chopper assembly. An adjustable photometer sampling window (15) was positioned over the whole MD plaque (consisting of ~15-20 cells), and emitted photons were detected by a Leitz photometer that was modified for photon counting. Magnification was ×400 by using an Olympus ×40 UVFL lens. Cells were loaded with the dye by adding SBFI-acetoxymethyl ester (AM; 20 µM) dissolved in DMSO to the luminal perfusate. The nonionic surfactant, Pluronic F-127 was added (1 mg/ml) to DMSO to facilitate loading, which required ~15 min, and then luminal SBFI-AM was removed. After a further ~15 min of exposure to the control perfusion solution, fluorescence intensities for both wavelengths stabilized at constant levels. SBFI fluorescence ratios (340/380 nm) were converted into [Na+]i values after permeabilizing of cell membranes on both sides of the tubule with 10 µM nigericin+monensin and equilibration of [Na+]i with ambient [Na+] in a stepwise manner between 0 and 150 mM. SBFI fluorescence was highly sensitive to the ambient [Na+] and was linear between 0 and 100 mM [Na+]i in both MD and cTAL cells.
Immunohistochemistry.
Rabbit kidneys were perfusion-fixed, and tissue sections were processed
as described earlier (15). Sections were blocked with goat
serum (1:25) and incubated for 1 h with the highly specific monoclonal antibody 6F (Developmental Studies Hybridoma Bank, University of Iowa; no dilution of the supernatant), which recognizes the Na-K-ATPase
1-subunit in various species
(2). This was followed by a 40-min incubation with
fluorescein-conjugated goat anti-mouse IgG (Vector Labs, 1:200).
Sections were mounted with Vectashield media containing
4,6-diamino-2-phenylindole (DAPI) for nuclear staining (Vector Labs).
Tissue sections were examined with an Olympus IX70 inverted
epifluorescence microscope using a UApo/340 ×40 objective. Images were
captured using a SenSys digital camera and IPLab Spectrum software
equipped with a power microtome (Signal Analytics).
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RESULTS |
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Transport-related dynamics of
[Na+]i in MD and cTAL
cells.
Resting [Na+]i in MD cells, in the presence
of 25 mM [NaCl]L and 150 mM NaCl in the bath, was
29.8 ± 4.4 mM (n = 12). As demonstrated in a
representative recording (Fig.
1A) and summarized in Fig. 1B, increasing [NaCl]L from 25 to 150 mM
caused a substantial increase in MD [Na+]i,
that plateaued at an [Na+]i of ~70 mM. In
contrast, baseline [Na+]i in adjacent cTAL
cells was 12.7 ± 1.6 mM (n = 16) and increased by
only 23.0 ± 6.9 mM in response to 150 mM [NaCl]L.
As depicted in Fig. 1B, addition of furosemide, a blocker of
Na+-2Cl-K+ cotransport, to the
lumen significantly reduced resting [Na+]i
and attenuated the [NaCl]L-induced elevations in
[Na+]i in both cell types. This finding
supports the notion that the primary mechanism for apical entry of NaCl
in MD and cTAL cells is the
Na+-2Cl
-K+ cotransporter. In
addition, as shown in Fig. 2, there is a
sigmoidal relationship between [Na+]i and
[NaCl]L, which plateaued at 60 mM [NaCl]L.
This is consistent with the known affinity of the cotransporter for
[Cl]L and is also consistent with the relationship
between [NaCl]L and TGF signaling. It should also be
mentioned, however, that 150 mM [NaCl]L, in the presence
of luminal furosemide, slightly but significantly increased
[Na+]i in both MD and cTAL cells, most
probably via the apical Na+/H+ exchanger NHE2.
Consistent with this suggestion is that the
Na+/H+ exchanger blocker HOE-642, like
furosemide, reduced both baseline [Na+]i and
the magnitude of 150 mM [NaCl]L-induced elevations in MD [Na+]i (Fig.
3). However, HOE-642 was less effective
compared with furosemide.
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Effect of ouabain on resting
[Na+]i in MD and cTAL
cells.
Addition of the Na-K-ATPase blocker ouabain to the bath did not
significantly change resting [Na+]i in MD
cells and had no effect on the MD [Na+]i
dynamics in response to increased [NaCl]L. In contrast,
bath ouabain significantly increased resting
[Na+]i in cTAL cells (Fig.
4) up to the level found in MD cells
(26.5 ± 6.7 mM, n = 6), and the 150 mM
[NaCl]L-induced increases in [Na+]i (plateau at 61.3 ± 13.6 mM) were
also similar to that found in MD cells. Importantly, the addition of 1 mM ouabain to the perfusate, in the continuous presence of bath
ouabain, significantly increased resting
[Na+]i in MD cells and caused a small but
further elevation in cTAL [Na+]i. Thus MD
cells (and also cTAL cells) possess an apical ouabain-sensitive Na+-efflux pathway. This is also supported by the
representative recording in Fig. 3, where luminal ouabain almost
completely blocked the recovery of [Na+]i
that occurs on the return to the low-[NaCl]L perfusate.
Thus these studies suggest that MD cells may possess an apically
located, ouabain-sensitive colonic H-K-ATPase.
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Luminal K+-dependent pH recovery in
MD cells.
To functionally identify the presence of a colonic form of the
H-K-ATPase at the apical membrane of MD cells, we used the experimental
maneuver illustrated in Fig.
5A. Removal of external Na+, K+, and Cl resulted in an MD
intracellular acidification to ~pH 6.8, as monitored by the
pH-sensitive dye
2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. In the
continued absence of external Na+ and K+, no
pHi recovery was detected. Readdition of only 5 mM
K+ to the perfusate, however, resulted in a significant
intracellular alkalinization, which is consistent with the presence of
an apical H+/K+ exchange mechanism. Subsequent
readdition of luminal Na+ caused a complete
pHi-recovery, most likely due to apical
Na+/H+ exchange. Figure 5B
summarizes studies in MD cells where the addition of ouabain to the
perfusate nearly abolished K-dependent pHi-recovery,
whereas Sch-28080 had no effect.
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Effect of ouabain on the resting
[Na+]i in the distal colon.
To functionally identify the H-K-ATPase in rabbit MD cells, it was also
necessary to characterize the pharmacological properties of the
H-K-ATPase located in the rabbit distal colon. Using an approach that
was similar to that used for the MD cells (Fig. 4), we measured changes
in resting [Na+]i in response to luminal
ouabain and Sch-28080 (Fig. 6). Bath ouabain increased intracellular [Na+]i,
presumably due to the existence of Na-K-ATPase at the basolateral membrane. Importantly, luminal ouabain, but not Sch-28080,
significantly increased resting [Na+]i, a
response that was similar to the one observed in MD cells.
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Immunohistochemical localization of the Na-K-ATPase
1-subunit.
As illustrated in Fig. 7A,
there was very little staining of the rabbit MD basolateral membrane
with an antibody directed toward the Na-K-ATPase
1-subunit. In contrast, adjacent cTAL cells and other
surrounding nephron segments were strongly positive at the basolateral
membrane.
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DISCUSSION |
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These studies examined apical transport-related dynamics of [Na+]i in MD and cTAL cells. At normal physiological conditions prevailing at the end of the cTAL and at the MD, [NaCl]L is ~20-25 mM. Resting [Na+]i in MD cells, in the presence of 25 mM [NaCl]L and 150 mM NaCl in the bath (with the assumption that normal interstitial fluid [Na+]) was ~30 mM. This value is significantly higher than that found in other renal epithelial cells, measured by others with similar methods (17), and in adjacent cTAL cells in the present study. In addition, 25-150 mM [NaCl]L-induced elevations in MD [Na+]i were far greater than found in cTAL cells, further suggesting that there are fundamental differences between these two cell types in terms of [Na+]i regulation. Also of particular importance, the [NaCl]L-induced elevation in MD [Na+]i was sensitive to [NaCl]L over the range of 0 to 60 mM [NaCl]L (Fig. 2). This is exactly the same dynamic range of [NaCl]L that induces TGF responses (4). Thus parallel changes in [NaCl]L, [Na+]i, and TGF sensitivity suggest that [Na+]i plays a vital role in MD cell signaling.
It has long been recognized that apical
Na+-2Cl-K+ cotransport is a major
NaCl-entry pathway in MD cells. However, with the identification of an
apical Na+/H+ exchanger, the relative
contribution of these two Na+-entry pathways has not been
determined. Using pharmacological inhibitors of cotransport
(furosemide) and Na+/H+ exchange (HOE-642), we
estimate that 80% of apical entry is through the cotransporter and
~20% is via the exchanger. Thus [Na+]i
dynamics in MD cells reflects, to a very large extent, the kinetic
properties and ion affinities of the cotransporter. The cotransporter
is therefore responsible for the sigmoidal relationship between
[NaCl]L and [Na+]i, with a
plateau of [Na+]i at a [NaCl]L
of 60 mM.
The representative recording in Fig. 1A demonstrates that
the [NaCl]L-induced elevation in MD
[Na+]i was reversible on return to low
[NaCl]L, suggesting that there is an active
Na+ extrusion mechanism. To rule out the possibility that
passive efflux, through the Na+/H+ exchanger or
Na+-2Cl-K+ cotransporter, was
responsible for Na+-efflux, we assessed
[Na+]i recovery in the presence of either the
Na+-2Cl
-K+ cotransport blocker
furosemide or the Na+/H+ exchanger inhibitor
HOE-642. Both agents failed to influence the recovery phase of
[Na+]i when [NaCl]L was
switched from 150 to 25 mM, thus providing a strong argument against
passive efflux and suggesting that there is an active Na+
extrusion process. The most likely candidate for this Na+
efflux is the Na-K-ATPase, and, indeed, ouabain almost completely blocked the Na+ recovery phase (Fig. 3). However, as shown
in Fig. 4, this effect of ouabain was unusual because it was effective
from the luminal and not the basolateral side, where Na-K-ATPase is
located. Because basolateral ouabain caused no significant change in
resting [Na+]i in MD cells, but significantly
increased resting [Na+]i in cTAL cells, the
difference in [Na+]i dynamics between these
two cell types can be explained by diminished Na-K-ATPase activity in
MD cells.
Functional identification of an H-K-ATPase in MD cells and its
localization to the apical membrane were evaluated by assessing ouabain-sensitive K+-dependent alkalinization on cell
acidification imposed by prior bilateral Na+ removal. This
experimental maneuver of cell acidification by removal of
Na+ has been described for MD cells by our laboratory
(15) and was also used in a previous study to characterize
H-K-ATPase activity in the cortical collecting tubule
(22). Addition of 5 mM luminal K+ resulted in
MD cell pHi recovery, and this recovery was abolished by
the addition of luminal ouabain (Fig. 5B). Because
K+ at a concentration of 5 mM was used in the lumen during
pH recovery, it is doubtful that there was significant proton efflux
due to changes in cell membrane potential. Also, previous patch-clamp experiments (9) showed that the apical K+
channel in MD cells is almost completely inhibited by intracellular acidification to a pH of 6.8. Thus this K+-dependent
pHi-recovery most likely occurred through the H-K-ATPase. Ouabain and Sch-28080 compounds are selective inhibitors for members of
the Na-K/H-K-ATPase family (10, 12, 25). Pharmacological profiles of members of this family have been very well documented on
the basis of studies in the rat or in expression systems using the
cloned rat protein. The Na-K-ATPase is inhibited by ouabain but is
insensitive to omeprazol, an inhibitor of the gastric H-K-ATPase, and
its derivative Sch-28080. Gastric H-K-ATPase is inhibited by both
omeprazol and Sch-28080, but not by ouabain, whereas nongastric H-K-ATPases are sensitive to ouabain, with certain isoforms showing sensitivity to very high concentrations of Sch-28080 (10, 12, 25). Drug sensitivity of the colonic H-K-ATPase in the rabbit has not yet been examined. Thus it was necessary to determine whether
the rabbit colonic H-K-ATPase had a pharmacological profile similar to
that found in other species such as the rat. Using an approach that was
similar to what was used for the MD cell studies, we isolated and
perfused individual crypts from distal colon and measured changes in
resting [Na+]i in response to luminal ouabain
and Sch-28080 (Fig. 6). The findings of these experiments suggest that
the H-K-ATPase, located in the rabbit distal colon, has a
pharmacological profile similar to that in the rat, i.e., sensitive to
ouabain but not Sch-28080 and, like MD cells, able to transport
Na+. Thus it can now be concluded that the
ouabain-sensitive but Sch-28080-insensitive luminal K-dependent
pHi recovery (Fig. 5B) indicates the presence of
an H-K-ATPase located at the apical membrane of MD cells that belongs
to the colonic isoform/subgroup. It is important to mention that all of
the preparations used in these studies were from animals kept on a
standard diet. This indicates constitutively active colonic H-K-ATPase
in MD cells, in contrast to the low-K+-diet-induced
isoforms in other nephron segments (7). Our functional studies are further supported by recent work (23) that
localized the HK2c protein (a splice variant of rabbit
colonic H-K-ATPase) at the apical membrane of MD cells using
immunohistochemistry. Another important aspect of the present work is
that it may shed some light on the functional properties of
HK
2c, because it has not yet been functionally expressed
in heterologous systems and characterized.
Further evidence for the scarcity of basolateral Na-K-ATPase
(1-subunit) in rabbit MD cells was obtained by
immunohistochemistry. The staining of the MD basolateral membrane with
an antibody directed toward Na-K-ATPase (Fig. 7A) was at the
limit of detection. This is direct support for our functional studies,
which demonstrated that bath addition of ouabain did not alter MD cell
[Na+]. These results are also consistent with recent
findings (1, 24) on the localization of the Na-K-ATPase
- and
-subunits in rat kidney. The
-subunit is a
tissue-specific regulator of the functional activity of Na-K-ATPase in
the kidney (1) and reduces the enzyme's affinities for
its major physiological ligands, Na+ and K+.
The
-subunit is highly expressed in MD cells at the basolateral membrane but, interestingly, is absent in adjacent cTAL cells (24). The colonic H-K-ATPase has been shown to assemble
with different
-subunits in heterologous systems (7, 10, 12, 25). The specific
-subunit involved in apical
Na(H)-K- ATPase in the MD remains to be determined. It should also be
mentioned that we have performed a number of studies using this same MD transport-measuring experimental protocol and have never found evidence
for a loss of cell polarity. Thus under these experimental conditions
it is very unlikely that ischemia caused rearrangement of
basolateral Na+ pumps to the apical membrane of the MD
cells in the isolated and perfused cTAL preparation.
In summary, we identified and localized, to the apical membrane of MD
cells, a colonic form of H-K-ATPase. Functional and immunological
evidence indicates that these cells do not express other K-ATPases,
suggesting that this colonic H-K-ATPase is the primary regulator of MD
cell [Na+]i. The interesting observation that
both Na+-influx and -efflux pathways are located at the
apical membrane in these polarized epithelial cells offers a novel
model of regulating cell [Na+]i, a
Na+-recycling mechanism. MD cells are not likely to be
primarily absorbing epithelia but rather function as sensor cells that
detect changes in [NaCl]L. The interesting finding is
that MD [Na+]i reflects changes in
[NaCl]L between 0 and 60 mM, a finding that is consistent
with the function of MD cells in TGF signaling. It should be mentioned
that the HK2 isoform knockout mouse has recently been
established (13), but TGF has yet to be examined. Further
studies are necessary to determine whether the MD apical H-K-ATPase
plays an important role in the sensor function of MD cells and in TGF
signaling. We speculate that it is the presence of H-K-ATPase and lack
of Na-K-ATPase that allows for such regulation of
[Na+]i in MD cells and thus allows
[Na+]i to reflect the luminal environment. We
further suggest that the expression of particular forms of this ATPase
family may be a generalized cellular mechanism that allows for
regulation and setting of cell [Na+]i. Thus
cells expressing the highly efficient Na-K-ATPase would have low
[Na+]i, cells expressing H-K-ATPase may have
higher [Na+]i, whereas cells expressing both
forms may have an intermediate level of
[Na+]i. Also, the recent findings of the
inhibitory
-subunit suggests that there may be need for other
Na+-efflux pathways during physiological inhibition of the
Na-K-ATPase to maintain [Na+]i.
Thus K-ATPases may have a generalized function in helping to set cell
[Na+]i. The fact that this pump works as an
Na(H)-K-ATPase is consistent with earlier studies (6, 8)
that examined Na+ transport via different isoforms of the
nongastric H-K-ATPase in expression systems and also with more recent
work (5, 16) using isolated apical membranes of rat distal
colon. Wide distribution of HK2 protein in distal colon
and nephron segments suggests that the colonic H-K-ATPase might
also have a yet unrecognized physiological importance in
Na+ transport and electrolyte homeostasis.
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ACKNOWLEDGEMENTS |
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We thank Dr. Strader (Schering-Plough Research Institute,
Kenilworth, NJ) for providing the Sch-28080. The antibody 6F was from the Developmental Studies Hybridoma Bank, University of Iowa.
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FOOTNOTES |
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We also thank Suzanne Randall, University of Alabama at Birmingham, Department of Surgery-Neurosurgery, for excellent help in tissue processing for immunohistochemistry.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-32032 (to P. D. Bell). J. Peti-Peterdi was a National Kidney Foundation Postdoctoral Fellow during these studies.
Address for reprint requests and other correspondence: J. Peti-Peterdi, 865 Sparks Ctr., 1720 Seventh Ave. South, Birmingham, AL 35294 (E-mail: petjan{at}uab.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 October 10, 2001; 10.1152/ajprenal.00251.2001
Received 15 August 2001; accepted in final form 4 October 2001.
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