Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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The tubular localization of
1,25-dihydroxyvitamin
D[1,25(OH)2D3]-stimulated calmodulin binding
proteins (CaMBP-Ds) in the rat kidney and the specificity of their
induction were characterized to better understand renal responses to
protracted 1,25(OH)2D3 treatment in vivo. None
of the other hormones tested (parathyroid hormone, calcitonin,
estradiol-17, testosterone, progesterone, hydrocortisone, or
dexamethasone) stimulated the CaMBP-Ds, whereas maximal
1,25(OH)2D3 stimulation occurred after a 5- to
7-day treatment with 100 ng/day 1,25(OH)2D3.
With the exception of the more ubiquitously distributed CaMBP-D150, the
CaMBP-Ds were localized in distal, but not proximal, tubule
preparations. 1,25(OH)2D3 induction of vitamin
D receptors and the CaMBP-Ds was similar with respect to dose-response
and time course. Finally, the CaMBP-Ds remained elevated for at least 4 wk after 1,25(OH)2D3 withdrawal. Because the
vitamin D-stimulated renal CaMBP-Ds are principally proteins of the
distal tubule, they may be associated with renal regulation of
Ca2+ homeostasis. The sustained induction of CaMBP-Ds is
important in addressing the question of whether their induction is a
function of normal Ca2+ homeostasis or a pathophysiological
consequence of hypervitaminosis D and hypercalcemia.
calmodulin; parathyroid hormone; calcitonin; calcium homeostasis; hypervitaminosis D
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INTRODUCTION |
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IN ADDITION TO ITS TRADITIONALLY recognized function of regulating plasma calcium levels, the vitamin D endocrine system exerts numerous pleiotropic effects unrelated to plasma Ca2+ homeostasis (13, 32, 44, 45). Moreover, many intracellular signaling molecules are affected by the hormonal form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D3], including calmodulin (CaM) and calmodulin binding proteins (CaMBPs) (2, 3). CaM is a ubiquitous regulator of cell function, and CaMBPs show broad tissue/cellular distribution patterns. Previous studies in the rat have provided evidence for four 1,25(OH)2D3-stimulated renal CaMBPs, designated CaMBP-D150, CaMBP-D110, CaMBP-D94, and CaMBP-D74 on the basis of molecular mass (2, 3). These CaMBP-Ds were selectively localized in the kidney (except for the widely distributed CaMBP-D150), showed varied patterns of subcellular distribution, and required protracted 1,25(OH)2D3 treatment in vivo for induction (2, 3). This requirement for protracted 1,25(OH)2D3 treatment may suggest that CaMBP-D stimulation is not a direct effect of the hormone but results from hypervitaminosis D-associated hypercalcemia.
1,25(OH)2D3 effects in the kidney include
regulation of the 1-hydroxylase and 24-hydroxylase enzymes in the
proximal tubule (1, 20, 24, 40) and stimulation of
calbindin-D28K and Ca2+ reabsorption in the
distal tubule (7, 11, 36, 41). The vitamin D receptors
(VDR) thought to mediate these effects are present in both tubular
segments (20, 23, 30). Colocalization of CaBP-D28 with
Ca2+-Mg2+-ATPase (8, 9) and the
similar localization of the Na+/Ca2+ exchange
system (35) in cells of the distal nephron have been interpreted as implicating roles for the
1,25(OH)2D3-VDR complex in regulating
Ca2+ transport therein. Moreover, studies of luminal vs.
basolateral membrane localization of the
Ca2+-Mg2+-ATPase (10, 19, 33) have
been important in implicating this pump in basolateral Ca2+
transport mechanisms in the distal nephron.
These studies were designed to characterize the localization of the CaMBP-Ds and the specificity of their induction to better understand renal responses to protracted 1,25(OH)2D3 treatment in vivo. The specificity of CaMBP-D stimulation was tested by comparing the effects of protracted treatment with a variety of steroid hormones and other hormones of the calcium-vitamin D axis. Because CaMBP functions and 1,25(OH)2D3 effects are specific to their tissue and cellular location, CaMBP-D localization was determined in proximal vs. distal tubules and in renal luminal vs. basolateral membrane preparations.
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MATERIALS AND METHODS |
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Animals.
Male weanling rats (21 days old, Sprague-Dawley strain, Charles River,
Madison, WI) were housed in incandescent light and fed a vitamin
D-deficient (D) diet containing 2.0% calcium, 1.25% phosphorous,
and 20% lactose (TD 87095, Teklad, Madison, WI). This dietary regimen
results in
D with normocalcemia after 6-8 wk, which is sustained
for at least 4-5 mo (26, 27). In these studies, rats
were maintained on the
D diet for 7 wk-5 mo before hormone treatment,
as described below; no differences in CaMBP-D induction were noted
across this time period. Rats were anesthetized with Nembutal before
decapitation. These procedures were approved by the Tulane University
Advisory Committee for Animal Resources.
Detection of CaMBPs. The 125I-labeled CaM gel overlay protocol used in these experiments was modified from the procedure developed by Glenney and Weber (18) and has been described in detail previously (2).
Isolation of nephron segments. The procedure used in these experiments is a modification of established methods (17, 28, 37, 43). Briefly, after rats were anesthetized, the kidneys were perfused with isosmotic modified Krebs-Henseleit buffer (KHB) solution that contained (in mM) 118 NaCl, 1.0 KH2PO4, 4.0 KCl, 27.2 NaHCO3, 1.25 CaCl2, 1.20 MgCl2, 5.0 glucose, and 10 HEPES, pH 7.4, until the venous effluent was clear, followed by a 5- to 10-min perfusion period with KHB containing collagenase (type V, 1,100 U/ml, Sigma, St. Louis, MO) and hyaluronidase (type III, Sigma, 400 U/ml). The kidneys were excised, and the capsules were removed. The cortical tissue was dissected out, minced, pooled from two rats/experiment, and subjected to further digestion with the KHB-enzyme solution for 20-30 min. After four to five washes with ice-cold KHB to remove the enzymes, the resulting pellet was resuspended in 40% isosmotic Percoll solution and centrifuged at 28,000 g for 30 min at 4°C. Three bands were routinely observed: a top band enriched in distal nephron segments, a reddish band immediately below made up of glomeruli, and a lower band enriched in proximal tubular segments. The bands of interest were removed and washed several times with KHB to remove the Percoll. The final pellet was resuspended in fresh KHB with 10% dialyzed calf serum in medium with amino acids, vitamins, and glutathione. The identity of the nephron segments was confirmed by light microscopy, and biochemical determination of specific enzyme markers, alkaline phosphatase for the proximal tubule and renal kallikrein for the distal tubule, was made. The purified nephron segments were homogenized, and the extracts were then assayed for CaMBPs by the 125I-CaM gel overlay procedure described above.
Isolation of luminal (brush-border) membranes. The isolation procedure is based on the procedure of Kinne-Saffran and Kinne (25). Briefly, a 10% suspension (wt/vol) of rat kidney cortex slices pooled from two to four rats/experiment was homogenized for 2 min at 4°C in mannitol buffer containing 10 mM mannitol, 2 mM Tris · HCl, pH 7.1, 0.1 mM phenylmethyl sulfonyl fluoride (PMSF), and 500 kallikrein inactivator units (KIU)/ml aprotinin. The homogenate was filtered through cheesecloth, and, while being mixed, CaCl2 was added to a final concentration of 10 mM. The suspension was kept on ice for 15 min, diluted 1:1 with mannitol buffer containing 10 mM CaCl2, and centrifuged at 500 g for 12 min. The pellet was discarded, and the supernatant was centrifuged at 15,000 g for 12 min. The resulting pellet, designated the crude brush-border membrane fraction, was resuspended in mannitol buffer with a Potter-Elvejhem homogenizer, and CaCl2 was added again to a final concentration of 10 mM. The suspension was kept on ice for 15 min, diluted 1:1 with mannitol buffer containing 10 mM CaCl2, and centrifuged at 750 g for 12 min. The pellet was discarded, and the supernatant was centrifuged at 15,000 g for 12 min, with the resulting pellet designated the purified brush-border membrane fraction. All homogenization, centrifugation, and dilution steps were carried out at 4°C. The purity of the isolated membranes was assessed by assaying for alkaline phosphatase, the luminal membrane enzyme marker, and Na+-K+-ATPase, the basement membrane enzyme marker. The isolated membranes were incubated on ice with Tris-EDTA-dithiothreitol (TED) buffer containing 0.02% Triton X-100 to allow solubilization of membrane proteins and then disrupted by sonication (Bronwill Scientific) before SDS-PAGE and 125I-CaM gel overlay as above.
Isolation of basolateral membrane. The isolation procedure is based on the method of Kinne-Saffran and Kinne (25). Briefly, renal cortical slices pooled from two to four rats/experiment were homogenized (5% wt/vol) with a Potter-Elvehjem homogenizer at 4°C in sucrose buffer consisting of 250 mM sucrose, 10 mM triethanolamine/HCl, pH 7.6, and 0.1 mM PMSF, and 500 KIU/ml aprotinin. The homogenate was diluted 1:2 with the sucrose buffer and centrifuged at 2,500 g for 15 min. The pellet was discarded, and the supernatant was centrifuged at 20,500 g for 20 min. The supernatant was removed carefully, and 5 ml of sucrose buffer were added to the top of the pellet and used to resuspend the upper fluffy layer of the pellet. The residual pellet and supernatant were discarded. Sucrose buffer (20 ml) was added to the retained fluffy layer before homogenization in a glass-Teflon homogenizer. The resulting homogenate represented the crude plasma membrane preparation. Percoll was added to the crude plasma membranes (8% vol/vol of membrane suspension) before centrifugation at 48,000 g for 30 min with the automatic brake off. Fractions between 13 and 17 ml from the top of the gradient were recovered, diluted 1:10 with sucrose-free buffer (10 mM triethanolamine/HCl, pH 7.4, 0.1 mM PMSF, and 500 KIU/ml aprotinin), and centrifuged at 48,000 g for 30 min. The final pellet was designated the purified basolateral membrane preparation. Its purity was assessed by assaying for the basolateral membrane marker enzyme Na+-K+-ATPase and the luminal membrane enzyme marker alkaline phosphatase. Before SDS-PAGE analysis, the isolated membranes were incubated on ice with TED buffer containing 0.02% Triton X-100 to allow solubilization of membrane proteins. The suspension was then disrupted by sonication before CaMBP analysis as above.
Enzyme markers. Alkaline phosphatase activity was measured with a Sigma 104 phosphatase substrate kit and expressed as Sigma units per milligram protein. Renal kallikrein activity was measured by the amidolytic assay of Marin-Grez et al. (31) as modified by El-Dahr and Yosipiv (14). Na+-K+-ATPase activity was determined by the procedure outlined by Post and Sen (34).
VDR assay. VDR levels were determined in renal crude chromatin preparations by the single-point [3H]1,25(OH)2D3 binding assay with 1 nM [3H]1,25(OH)2D3 and 1 µM unlabeled 1,25(OH)2D3, as previously described (16).
Chemicals. Electrophoresis chemicals were purchased from Bio-Rad Laboratories (Hercules, CA), and hormones, enzymes, and protease inhibitors were from Sigma. 125I-CaM (65-100 µCi/µg) was purchased from DuPont/NEN (Wilmington, DE). All other chemicals were reagent grade.
Data analysis and statistical treatment. Densitometric analysis of the autoradiographs was done as previously described (2). These data and the data obtained from the VDR assay were subjected to analysis by ANOVA or Student's t-test (2 groups).
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RESULTS |
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Steroid hormone effects on renal CaMBP-Ds.
To determine whether treatment by steroid hormones results in CaMBP
stimulation in rat renal cytosol, D rats were treated with either
vehicle or 100 ng 1,25(OH)2D3, or 1 mg
estradiol-17
, testosterone, progesterone, or hydrocortisone, or 0.4 mg dexamethasone daily for 7 days before analysis of the renal CaMBPs
by the 125I-CaM gel overlay procedure. The results
demonstrate that the four vitamin D-related CaMBP-Ds are not stimulated
by the other test steroids under these conditions (Fig.
1). However, dexamethasone treatment
resulted in detection of a 60-kDa CaMBP not seen with any other
treatment.
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PTH and calcitonin vs. renal CaMBP-Ds.
To determine the effect of other calcium-regulating hormones on
rat renal CaMBP profiles, the effects of PTH and calcitonin were
tested. Because the biological effects of the membrane effectors PTH
and calcitonin occur more rapidly than those of
1,25(OH)2D3, CaMBPs were assessed after 1, 4, and 24 h and after 7-day treatment with these peptide hormones.
The results demonstrate that neither short-term (1- to 4-h) nor
long-term (1- to 7-day) treatment with these hormones alters the CaMBP
patterns in rat renal cytosolic preparations (Fig.
2). In particular, there was no effect of
PTH or calcitonin on the four
1,25(OH)2D3-stimulated CaMBP-Ds.
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Nephron localization of CaMBP-Ds.
Because 1,25(OH)2D3 exerts different
effects on cells of the proximal and distal tubules, these
nephron segments were isolated (Table 1)
and CaMBP-Ds were determined therein. Light microscopic examination
indicated very minimal glomerular contamination of these tubular
fractions. Consistent with the previously described generally
ubiquitous distribution, there were 150-kDa CaMBPs in both proximal and
distal tubular fractions (Fig. 3). With
the exception of CaMBP-D150, CaMBP-Ds were localized to the distal tubular nephron segment (Fig. 3).
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Membrane localization of CaMBP-Ds.
Because some CaMBPs are localized to the luminal vs. basolateral
membranes, these membrane fractions were purified (Table 2) to test the distribution of CaMBP-Ds.
CaMBPs at 150 kDa were present in most fractions, but the induced
CaMBP-D150 and CaMBP-D94 were predominantly present in the cytosolic
fraction (Fig. 4). Additionally, none of
the CaMBP-Ds were present in the basolateral membrane preparations
(Fig. 4). Conversely, the purified luminal membrane preparations
contained a noninduced CaMBP at 135 kDa and low levels of CaMBP-D110
and CaMBP-D74.
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CaMBP-D induction vs. VDR stimulation.
To compare the parameters of CaMBP-D induction to another
well-established 1,25(OH)2D3 effect in the
kidney, the time course and dose-response of VDR stimulation and
CaMBP-D induction were compared after
1,25(OH)2D3 treatment. Induction of
CaMBP-D94 was selected for quantitation for this comparison, in part
because CaMBP-Ds show rather similar patterns of
1,25(OH)2D3 induction (2). After a
brief lag in CaMBP-D94 induction at 24 h, which might
reflect differences in assay sensitivity at low levels, stimulation of
renal VDR levels vs. CaMBP-D94 levels was not significantly different
through the 1- to 7-day 1,25(OH)2D3 treatment
period (Fig. 5A). Moreover,
there was no difference in the pattern of 1,25(OH)2D3-dose responsiveness of VDR and
CaMBP-D94 stimulation after 7 days of treatment (Fig. 5B).
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Effect of 1,25(OH)2D3 treatment on
physiological parameters.
To better understand CaMBP-D induction, the physiological status of the
animals was assessed over the 1- to 7-day
1,25(OH)2D3 treatment period. As shown in Table
3, there were no significant changes in
rat body weight or in kidney weight under these treatment conditions.
Conversely, plasma Ca2+ levels increased
significantly during this treatment, in parallel to the increases in
both CaMBP-D94 and VDR levels.
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Sustained CaMBP-D levels after cessation of
1,25(OH)2D3 treatment.
To further examine the relationship between renal CaMBP-Ds and
1,25(OH)2D3 treatment, CaMBP-Ds were assessed
1-4 wk after the end of the 7-day
1,25(OH)2D3 induction regimen. These
experiments indicate that the levels of all four CaMBP-Ds remain
elevated throughout the 1- to 4-wk test period after
1,25(OH)2D3 withdrawal (Fig.
6). Similarly, a preliminary assessment
of VDR levels also indicated little change in VDR levels over this
time: 2,656 fmol/mg DNA after 7-day 1,25(OH)2D3
treatment vs. 2,331 fmol/mg DNA 1 wk after
1,25(OH)2D3 withdrawal vs. 2,940 fmol/mg DNA 4 wk after withdrawal.
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DISCUSSION |
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These data establish that stimulation of CaMBP-Ds in rat kidney after protracted 1,25(OH)2D3 treatment is a sustained effect. Moreover, CaMBP-D stimulation exhibits specificity in that the effects result from 1,25(OH)2D3 treatment or its sequelae and do not follow treatment with a number of other hormones.
Because CaMBP-D induction requires protracted
1,25(OH)2D3 treatment (2), which
is accompanied by elevations in plasma Ca2+ levels (Table
3), it was important to determine the effects of other
calcium-regulating hormones on CaMBP patterns. Moreover, because PTH
and calcitonin are peptide hormones with a more rapid onset of action
vs. that of 1,25(OH)2D3-induced nuclear
transactivation events, their effects were studied at both early
(1-4 h) and late (1-7 day) time periods. Despite this rather
broad temporal window of observation, neither PTH nor calcitonin
treatment in D rats altered the renal CaMBP patterns at any time tested.
Whether 1,25(OH)2D3 stimulation of rat renal
CaMBPs represented a general effect of steroid hormonal interactions
with their receptors was addressed. An additional impetus for these
studies was a precedent for steroid hormones altering the expression of CaMBPs in at least one system, where reduced Ca2+-CaM
binding to a 51-kDa protein occurred during estrogen treatment in the
human breast cancer cell line ZR-75-1 (29). The
present studies demonstrated no effect on renal CaMBP-Ds after
treatment with the sex steroids estradiol-17, testosterone, and
progesterone nor with the glucocorticoids dexamethasone and
hydrocortisone (Fig. 1). However, dexamethasone treatment did result in
induction of an unidentified 60-kDa CaMBP (Fig. 1). These results
demonstrate that the stimulation of renal CaMBP-Ds is a specific
consequence of 1,25(OH)2D3 or its effects in
rat kidney. Furthermore, the fact that major CaMBP-Ds were present only
in 1,25(OH)2D3-treated groups likely rules out
nonspecific stress factors, such as those that might be associated with
hypervitaminosis D, in the stimulation of renal CaMBP-Ds.
Understanding the specific tubular localization of each of the rat
renal CaMBP-Ds can provide important information about their function
and identity. The nephron localization studies indicated that, whereas
150-kDa CaMBPs were uniformly distributed in proximal and distal
tubular segments (Fig. 3),
1,25(OH)2D3-stimulated CaMBP-D150 was
predominantly located in proximal tubular preparations, where the
principal function of 1,25(OH)2D3 is to
regulate 1- and 24-hydroxylase activities. In contrast, CaMBP-D110,
CaMBP-D94, and CaMBP-D74 are predominantly localized to distal tubular
segments. The selective localization of CaMBP-D110, CaMBP-D94, and
CaMBP-D74 to the distal tubule, where vitamin D-dependent
calbindin-D28K is also localized (8), suggests
that these proteins may be associated with some aspect of the
hormone-regulated calcium translocation mechanisms in this segment of
the nephron.
CaMBP-Ds were initially discovered in cytosol preparations of rat kidney (2, 3). However, they may represent readily extracted membrane proteins, as suggested in part by the partial localization of CaMBP-D150 and CaMBP-D110 in crude particulate fractions (Fig. 4 and Ref. 2). Two CaMBPs related to functions of vitamin D (4, 5, 12, 22, 46) were previously localized to specific cellular membrane poles, i.e., the 136-kDa plasma membrane Ca2+-ATPase in renal basolateral membranes (8, 19, 35) and the 110-Da brush-border myosin 1 (BBM 1) protein in luminal membranes of chick intestinal cells (5, 6, 21). Thus it was important to determine whether the CaMBP-Ds could be detected in purified renal basolateral and luminal membrane preparations. In these studies, neither CaMBP-D150 nor CaMBP-D94 was present in purified membrane preparations. However, there were low levels of both CaMBP-D110 and CaMBP-D74 in luminal membrane preparations (Fig. 4). The discrepancy between this observation and the apparent cytosolic location of CaMBP-D74 (Fig. 4 and Ref. 2) may result from the more highly purified nature of luminal and basolateral membrane preparations. Moreover, the presence of renal CaMBP-D110 in luminal membranes suggests that this CaMBP-D may be similar to 110-kDa chick intestinal BBM 1 (5, 6, 21). However, whether there is any association of luminal membrane CaMBP-D74 with CaMBP-D110 and its functions remains a question for future studies.
One of the important aspects of CaMBP-D stimulation by 1,25(OH)2D3 in this system is the protracted treatment period required for the effect, resulting in the question of whether CaMBP-D stimulation is a function of 1,25(OH)2D3 treatment per se or a consequence of other events that result from hypervitaminosis D. To begin to address this issue, CaMBP-D stimulation was compared with a well-known effect of 1,25(OH)2D3 in the kidney, i.e., increased VDR levels. The results of this comparison indicated that, after a brief lag in CaMBP-D levels, CaMBP-D and VDR levels exhibited very similar patterns of time course and dose responsiveness. The parallel in 1,25(OH)2D3 stimulation of these parameters is consistent with the hypothesis that CaMBP-D stimulation is a 1,25(OH)2D3-induced response with possible roles in renal regulation of Ca2+ homeostasis or in the adaptation of the kidney to long-term 1,25(OH)2D3 stimulation. Moreover, these effects parallel increases in plasma Ca2+ levels under these conditions. Thus the alternative hypothesis that CaMBP-D stimulation results from hypercalcemia or other consequences of hypervitaminosis D cannot be ruled out. In the event of hypercalcemic induction of renal CaMBP-Ds, the parallel increase in VDR levels would be maladaptive (42). Moreover, if elevated plasma Ca2+ is the direct stimulus, renal CaMBP-D induction is a very early response to elevated plasma Ca2+ levels or nephrocalcinosis and/or a highly specific effect of hypercalcemia on the kidney. In part, the latter conclusion results from the observations that parallel changes in CaMBPs were not observed in the heart (Ref. 3; Siaw EKO and Walters MR, unpublished observations), another tissue that is particularly sensitive to calcemic damage (38, 39, 47).
In conclusion, these studies indicate that, with the exception of CaMBP-D150, vitamin D-stimulated renal CaMBP-Ds are principally proteins of the distal tubule and thus may be associated with renal regulation of Ca2+ homeostasis. Whether specific induction of the CaMBP-Ds by protracted vitamin D treatment is a function of normal Ca2+ homeostasis or a pathophysiological consequence of the attendant hypercalcemia remains an important area for future study.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-43846.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. R. Walters, Dept. of Physiology SL39, Tulane University School of Medicine, New Orleans, LA 70112. (E-mail:mwalters{at}tulane.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.
10.1152/ajprenal. 00286.2000
Received 18 September 2000; accepted in final form 30 July 2001.
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