Departments of 1 Pediatrics and 2 Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9063
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ABSTRACT |
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The early proximal tubule preferentially
reabsorbs organic solutes and bicarbonate over chloride ions, resulting
in a luminal fluid with a higher chloride concentration than that in
blood. From this late proximal tubular fluid, one-half of NaCl
reabsorption by the adult proximal tubule is active and transcellular
and one-half is passive and paracellular. The purpose of the present in
vitro microperfusion study was to determine the characteristics of
passive chloride transport and permeability properties of the adult and neonatal proximal straight tubules (PST). In tubules perfused with a
late proximal tubular fluid, net passive chloride flux was 131.7 ± 37.7 pmol · mm1 · min
1
in adult tubules and
17.1 ± 23.3 pmol · mm
1 · min
1 in
neonatal proximal tubules (P < 0.01). Chloride
permeability was 10.94 ± 5.21 × 10
5 cm/s in
adult proximal tubules and
1.26 ± 1.84 × 10
5 cm/s in neonatal proximal tubules (P < 0.05). Thus neonatal PST have a chloride permeability not different
from zero and have no net passive chloride transport. Bicarbonate
permeability is also less in neonates than adults in this segment
(
0.07 ± 0.03 × 10
5 vs. 0.93 ± 0.27 × 10
5 cm/s, P < 0.01).
Neonatal PST have higher sodium-to chloride and bicarbonate-to-chloride
permeability ratios than adult PST. However, mannitol and sucrose
permeabilities were not different in adult proximal tubules and
neonatal PST. Transepithelial resistance was measured using current
injection and cable analysis. The resistance was 6.7 ± 0.7
· cm2 in adult tubules and 11.3 ± 1.4
· cm2 in neonatal PST (P < 0.01). In conclusion, there are significant maturational changes in the
characteristics of the PST paracellular pathway affecting transport in
this nephron segment.
chloride transport; renal development; passive transport; tight junction; chloride permeability; bicarbonate permeability
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INTRODUCTION |
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THE EARLY PROXIMAL TUBULE preferentially reabsorbs glucose, amino acids, and bicarbonate over chloride ions (18, 25). This leaves the luminal fluid in the late proximal tubule with a lower bicarbonate concentration and higher chloride concentration than that in the peritubular plasma (18, 25). In proximal tubules perfused with a high-chloride-low-bicarbonate solution without organic solutes simulating late proximal tubular fluid, approximately one-half of NaCl transport is active and transcellular and one-half is passive and paracellular (3, 4, 28, 29). Active NaCl transport is mediated by the parallel operation of the sodium/hydrogen exchanger and a chloride/base exchanger (3, 28).
Passive chloride transport is mediated by passive diffusion of chloride down its electrochemical gradient across the paracellular pathway (1, 4, 16). The magnitude of passive chloride transport is not only dependent on the chloride concentration gradient that develops by the late proximal tubule but also the permeability properties of the paracellular pathway. We have recently compared the rates of volume absorption in neonatal and adult proximal straight tubules (PST) perfused with a high-chloride solution simulating late proximal tubular fluid and bathed in a serumlike albumin solution (28, 29). The rate of volume absorption was higher in adult PST than in neonatal tubules (28, 29). The rate of volume absorption in adult PST was also higher when active transport was inhibited with bath ouabain (28, 29). The higher rate of passive volume absorption in adult PST than in neonatal tubules was consistent with a maturational change in the paracellular pathway that may affect net chloride transport in this segment. The purpose of the present study was to directly determine whether there are developmental changes in the PST paracellular pathway that impact passive chloride transport.
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METHODS |
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Animals. Pregnant New Zealand White rabbits arrived at our institution at least 4 days before their expected date of delivery. Neonatal rabbits were cared for by their mothers and were studied between 17 and 22 days of age. Adult animals were at least 8 wk of age.
In vitro microperfusion flux studies. Isolated segments of superficial PST were perfused as previously described (4, 5, 28, 29). Briefly, tubules were dissected in Hanks' balanced salt solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 0.44 KH2PO4, 1 MgCl2, 10 Tris, 0.25 CaCl2, 2 glutamine, and 2 L-lactate at 4°C. Tubules were transferred to a 1.2-ml temperature-controlled bath. The tubules were perfused using concentric glass pipettes.
PST were perfused at ~10 nl/min. For flux studies, the bathing solution was a serumlike albumin solution containing (in mM) 115 NaCl, 25 NaHCO3, 2.3 Na2HPO4, 10 Na acetate, 1.8 mM CaCl2, 1 MgSO4, 5 KCl, 8.3 glucose, and 5 alanine as well as 6 g/dl bovine serum albumin. The osmolality of these solutions were adjusted to 295 mosmol/kgH2O. The pH and osmolality of the bathing solution were maintained constant by continuously changing the bath at a rate of 0.5 ml/min. Net volume absorption (JV; in nl · mmMeasurement of neonatal superficial proximal convoluted tubule transport. In the first series of experiments, we examined whether the superficial proximal convoluted tubule (PCT) could generate a higher luminal chloride than the glomerular ultrafiltrate or the blood as in the adult (18, 25). We perfused outer superficial and surface neonatal PCT with an ultrafiltrate-like solution containing (in mM) 115 NaCl, 25 NaHCO3, 2.3 Na2HPO4, 10 Na acetate, 1.8 mM CaCl2, 1 MgSO4, 5 KCl, 8.3 glucose, and 5 alanine at 5 nl/min. The chloride concentration in the initial luminal and collected fluid were measured using the microtitration method of Ramsay (24), and net chloride flux was determined.
Measurement of neonatal and adult chloride permeability and transport in PST. In the second series of experiments, we examined net chloride flux and chloride permeability in PST from neonatal and adult rabbits. Tubules were perfused with a high-chloride solution simulating late proximal tubular fluid containing (in mM) 140 NaCl, 5 NaHCO3, 5 KCl, 4 Na2HPO4, 1 CaCl2, and 1 MgSO4. The bath chamber was cooled to 20°C to inhibit active transport (5).
The chloride concentrations were measured to determine the net passive chloride flux and chloride permeability. Net passive chloride flux was determined using the following equation
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Measurement of mannitol and sucrose permeability in neonatal and adult PST. In the next series of experiments, we measured mannitol and sucrose permeabilities (Pmann) and (Psucrose) in neonatal and adult PST. PST were perfused with a solution containing (in mM) 10 mannitol (or 10 sucrose), 110 NaCl, 30 Na gluconate, 5 NaHCO3, 5 KCl, 1 Na2HPO4, 1.8 CaCl2, 1 MgSO4, 1 acetazolamide, and 25 µCi/ml [14C]mannitol (or [14C]sucrose). Tubules were bathed in a serumlike albumin solution at 37°C. We previously showed that under these conditions the rate of volume absorption was not different from zero (23, 27).
Pmann was calculated using the equation below (23, 27)
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Measurement of sodium-to-chloride and bicarbonate-to-chloride
permeability ratios.
In the next series of experiments, we measured the relative
sodium-to-chloride permeability
(PNa/PCl) and
bicarbonate-to-chloride permeability ratios
(PHCO3/PCl) in neonatal
and adult PST. Tubules were perfused with the ultrafiltrate-like
solution shown in Table 1 and bathed in
an ultrafiltrate-like solution at 37°C.
PNa/PCl and
PHCO3/PCl were calculated
from the passive transepithelial PD due to ion concentration gradients
as previously described (6, 13, 31). After incubation with
the ultrafiltrate-like solution, the bathing solution was changed to
the NaCl dilution solution, and the transepithelial PD was measured.
The bathing solution was then changed to a sodium bicarbonate dilution
solution, and the transepithelial PD was measured. All bathing
solutions contained 105 M ouabain to inhibit any
transepithelial PD generated from active transport. The composition of
the bathing and luminal solutions are shown in Table 1. The
transepithelial PD was corrected for the small liquid junction
potentials due to asymmetrical luminal and bath solutions as described
by Berry and Rector (7).
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Measurement of transepithelial resistance.
The specific resistance (Rm) was measured as
described by Berry (6). Briefly, PST from adult and
neonatal New Zealand White rabbits were perfused and bathed with
Hanks' solution at 37°C. Tubules were perfused with a
double-barreled pipette made from theta glass (Hilgenberg Glass,
Hilgenberg, Germany). One barrel of the pipette was used to measure the
PD at the perfusion end (PD0), while the other barrel was
used to pass current (30-60 nA) using a Grass S44 stimulator
(Grass Instruments, Quincy, MA) via silver wire. The current injected
was measured with a Keithley 617 programmable electrometer (Keithley
Instruments, Cleveland, OH). A KCl/KNO3-agarose bridge was
also placed in the collecting end to measure the voltage deflection at
the distal end of the tubule (PDL). The
potential difference measurements were recorded on a Linseis, L6512B
(Linseis, Princeton, NJ) two-channel chart recorder. The coupling
resistance was determined by measuring the voltage deflections at the
perfusion and collection ends with no tubule present. These voltage
deflections were subtracted from the readings with the perfused tubule
in place and are represented in the equations below by
PD0 and
PDL for the corrected voltage deflection at the perfusion and collection ends, respectively.
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RESULTS |
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The first series of experiments was designed to determine whether
the neonatal superficial PCT could generate a chloride gradient by
preferentially absorbing solutes over chloride ions, as has been
determined in the adult nephron (18, 25). The average tubule length was 1.1 ± 0.1 mm. Neonatal superficial PCT
(n = 5) perfused with an ultrafiltrate-like solution
absorbed fluid at a rate of 0.48 ± 0.08 nl/mm and had a
transepithelial PD of 2.0 ± 0.6 mV. The initial chloride
concentration in the perfusate was 111.4 ± 1.3 meq/l and rose to
122.0 ± 2.2 meq/l in the collected fluid (P < 0.01). Despite the high rate of volume absorption, there was virtually
no chloride transport (5.9 ± 8.3 pmol · mm
1 · min
1). Thus
the superficial proximal tubule has preferential absorption of solutes
over chloride and delivers a solution with a higher luminal
chloride than the ultrafiltrate to the PST.
We have previously shown that the rate of volume absorption in neonatal
PST perfused with a high chloride solution simulating late proximal
tubule fluid was less than that in the adult (28, 29). We
also perfused PST with an ultrafiltrate-like solution to determine
whether there was a maturational change in transport from an
ultrafiltrate-like solution. Adult PST (n = 6) had a
rate of volume absorption of 0.44 ± 0.13 nl · mm1 · min
1 compared
with
0.02 ± 0.03 nl · mm
1 · min
1 in neonatal
PST (P < 0.05). Thus the rate of volume absorption in
the neonatal PST is less than that of the adult from an ultrafiltrate and late proximal tubule solution.
The next series of experiments was designed to examine whether there
was a maturational change in chloride permeability and passive chloride
flux in the PST. PST were perfused with a high chloride solution
simulating late proximal tubular fluid and bathed in a serumlike
albumin solution at 20°C to inhibit active transport. The rate of
volume absorption in neonatal PST was 0.08 ± 0.05 nl · mm1 · min
1, which was
less than the 0.39 ± 0.09 nl · mm
1 · min
1 measured in
adult proximal tubules (P = 0.01). The transepithelial PD was 0.7 ± 0.5 mV in neonatal PST and 3.7 ± 0.3 mV in
adult tubules (P < 0.001). The developmental changes
in chloride flux and chloride permeability are shown in Fig.
1. Net chloride flux was
17.1 ± 23.3 pmol · mm
1 · min
1 in
neonatal proximal tubules and 131.7 ± 37.7 pmol · mm
1 · min
1 in adult
tubules (P < 0.01). Chloride permeability was
1.26 ± 1.84 × 10
5 cm/s in neonatal proximal
tubules and 10.94 ± 5.21 × 10
5 cm/s in adult
proximal tubules (P < 0.05). Thus neonatal PST have a
chloride permeability not different from zero and have no net passive
chloride transport.
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We also compared bicarbonate permeability in neonatal and adult PST.
Tubules were perfused with a solution containing a bicarbonate concentration of 5 meq/l while there was 25 meq/l bicarbonate in the
bathing solution. Bicarbonate permeability was 0.93 ± 0.27 × 105 cm/s in adult PST (n = 6) and
0.07 × 10
5 in neonatal PST (n = 5; P < 0.01). Thus bicarbonate permeability is
also higher in the adult than in the neonatal PST.
In the next series of experiments, we examined whether there was a
developmental change in Pmann. In these
experiments, tubules were perfused with a solution that results in no
net volume flux (23, 27). The rate of volume absorption in
neonatal and adult proximal tubules was 0.12 ± 0.05 and
0.03 ± 0.05 nl · mm
1 · min
1,
respectively (P = NS). Mannitol is a sugar that is not
actively transported and is not metabolized. The results of these
experiments are shown in Fig. 2.
Pmann was 6.63 ± 2.23 × 10
6 in adult proximal tubules and 5.64 ± 1.21 × 10
6 cm/s in neonatal proximal tubules. Similarly,
Psucrose was 4.22 ± 1.11 × 10
6 in adult PST and 4.20 ± 1.50 × 10
6 cm/s in neonatal PST (n = 6 for
both). Thus there were no differences in Pmann
and Psucrose between neonatal and adult PST.
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The next series of experiments were designed to determine the relative
PST passive permeability of sodium and bicarbonate compared with
chloride ions. The results of these experiments are shown in Figs.
3 and 4. As
can be seen, both PNa/PCl
and PHCO3/PCl were
significantly lower in adult than in neonatal PST. Adult proximal
tubules were more permeable to chloride than to sodium ions, whereas
the relative permeability of the neonatal PST was not different from
one. In both the neonatal and adult PST, chloride was more permeable
than bicarbonate ions. However,
PHCO3/PCl was greater in
the neonate tubules.
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In the final series of experiments, we examined whether there was a
maturational change in transepithelial resistance. These results are
shown in Fig. 5. The transepithelial
resistance was 6.7 ± 0.7 · cm2 in adult
tubules and 11.3 ± 1.4
· cm2 in neonatal
PST, respectively (P < 0.01). Thus there is a
maturational decrease in transepithelial resistance in this segment.
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DISCUSSION |
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The present study examined the passive permeability properties of the neonatal PST. Compared with adult PST, neonatal PST have a lower rate of passive chloride transport due to a lower permeability of the PST to chloride ions. Bicarbonate permeability was also less in the neonatal PST than the adult PST. PNa/PCl and PHCO3/PCl were both greater in neonatal than in adult PST. The transepithelial resistance was significantly higher in neonatal PST than in adult PST. However, there were no differences in the Pmann and Psucrose between neonatal and adult PST.
As with the mature kidney, the neonatal kidney must reclaim the vast majority of the filtered chloride. We have recently examined the relative rates of volume absorption from a high-chloride perfusate simulating late proximal tubular fluid (28, 29). The rate of volume absorption was greater in adult tubules in the presence and absence of active transport (28, 29). Active NaCl transport in this segment is mediated by the parallel operations of luminal sodium/hydrogen and chloride/base exchangers in both the adult and neonatal segments (28). There was an approximately fivefold increase in the rate of both sodium/hydrogen and chloride/base exchanger activity during postnatal development of the rabbit PST, which accounts for the maturational increase in active NaCl transport in this segment. The present study directly demonstrates that the lower rate of passive volume absorption in neonatal tubules was due to lower chloride permeability, resulting in a lower rate of passive paracellular chloride transport.
Maturational changes in passive transport have received little attention. In a previous study, Kaskel et al. (15) injected sucrose, creatinine, and mannitol into early proximal tubules of neonatal and adult guinea pigs and measured the urinary recovery from the ipsilateral kidney. While urinary recovery of sucrose and creatinine did not vary with age and was comparable to inulin, mannitol recovery increased from 92% at 1 day of age to 100% at 49 days of age. While these studies were indirect and assessed mannitol absorption along the entire nephron, these data were consistent with a maturational decrease in paracellular pathway permeability to small molecules such as mannitol. In addition, Horster and Larsson (14) found that there was passage of microperoxidase into the intercellular spaces of rabbit proximal tubules perfused under a transtubular hydrostatic pressure of 20 cmH2O. However, this study did not find differences in the appearance in the lateral cellular spaces and tight junctions between neonatal and adult rabbit proximal tubules when they were examined using electron microscopy.
Our data seem to be at variance with these previous findings. We found that the neonate had a lower permeability to chloride and bicarbonate and a higher transepithelial resistance. There was no difference in PST Pmann and Psucrose in our study. The difference between our findings and previous studies may reflect a difference in techniques used to assess paracellular permeability. It is also possible that the maturational changes in permeability predominantly affect anions such as chloride and bicarbonate. However, it should be noted that the present study directly measured chloride and bicarbonate permeabilities and PST resistance showing a maturational increase in chloride and bicarbonate permeabilities and decrease in resistance in the PST.
Compared with the distal nephron, the proximal tubule is a low-resistance epithelium. In this study, we used current injection and cable analysis to determine the relative resistance of the neonatal and adult proximal tubule using methods comparable to those previously described (6, 17, 19). We found that the resistance of the PST was higher in neonatal PST than in adult PST, consistent with a maturational change in the properties of the paracellular pathway. The reason there was not an inverse change in the Pmann and Psucrose and resistance during development is unclear.
The preferential reabsorption of bicarbonate over chloride ions by the early proximal tubule results in an ion gradient favoring chloride absorption and bicarbonate secretion. The relative rates of chloride absorption to bicarbonate secretion are dependent on the PHCO3/PCl of the PST. The lumen positive PD in tubules perfused with a high-chloride-low-bicarbonate perfusate simulating late proximal tubular fluid is consistent with a PHCO3/PCl of less than one, which was measured in both adult and neonatal PST. The magnitude of the lumen positive transepithelial PD was greater in adult tubules and was consistent with a lower PHCO3/PCl in the mature tubule than in that of the neonate. There was a maturational decrease in PHCO3/PCl that was a reflection of the change in properties of the paracellular pathway. The increase in chloride permeability results in a developmental increase in passive chloride transport.
The dilution potential measurement of PHCO3/PCl measures the relative permeabilities and not their actual value. The measured chloride permeability in the neonate was slightly negative, and it might be questioned how a permeability could be negative. Direct measurement of chloride permeability, while negative, was not different from zero in the neonatal PST, which was very different from the high permeability in the adult PST.
We also examined whether there was a maturational change in the relative PNa/PCl during development. While adult proximal tubules have a greater chloride than sodium permeability, this was not true of neonatal tubules. As speculation, these data suggest that there may be maturational changes in the paracellular pathway that result in greater anion/cation permeability as the tubule matures.
The changes in the permeability properties of the paracellular pathway are likely mediated by a change in the composition of tight junctional proteins. The tight junction creates the primary permeability barrier to diffusion of solutes across the paracellular pathway. Recently, several protein components of the tight junction have been identified and characterized (2, 8, 21). Of potential relevance are occludin and claudin proteins, which are localized to junctional fibrils and are the transmembrane component of tight junctions (9-11, 20, 26, 30). Both occludin and claudins have four transmembrane domains and two extracellular loops, which form a seal at the tight junction between neighboring cells (9-11, 20, 26, 30). Unlike occludin, there are several claudin isoforms (9, 11, 22, 30). Different claudin isoforms have been found to have different tissue distributions (22). It is possible that the permeability changes seen during postnatal maturation are due to developmental changes in the abundance of occludin or claudin or a maturational change in the claudin isoforms that constitute the tight junctional strands. As speculation, the higher resistance and lower permeability of chloride ions in neonatal PST compared with adults could be due to a maturational decrease in a claudin with net negative charges on the extracellular loops.
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ACKNOWLEDGEMENTS |
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We are grateful for the secretarial assistance of Janell McQuinn. We also acknowledge the assistance of Drs. Al Rouch and Jim Shafer in establishing the methodology to measure transepithelial resistance in our laboratory.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Disease Grant DK-41612 (to M. Baum).
Address for reprint requests and other correspondence: M. Baum, Dept. of Pediatrics, UT Southwestern Medical Ctr., 5323 Harry Hines Blvd., Dallas, TX 75390-9063 (E-mail: mBaum{at}mednet.swmed.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.
April 16, 2002;10.1152/ajprenal.00005.2002
Received 3 January 2002; accepted in final form 9 April 2002.
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