1 Department of Medicine, 3 Department of Physiology, University of Florida and 2 Nephrology Section, Department of Veterans Affairs Medical Center, Gainesville, Florida 32610-0224
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ABSTRACT |
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The purpose of this study was to examine
cation channel activity in the apical membrane of the outer medullary
collecting duct of the inner stripe (OMCDi) using the
patch-clamp technique. In freshly isolated and lumen-opened rabbit
OMCDi, we have observed a single channel conductance of
23.3 ± 0.6 pS (n = 17) in cell-attached (c/a)
patches with high KCl in the bath and in the pipette at room
temperature. Channel open probability varied among patches from
0.06 ± 0.01 at 60 mV (n = 5) to 0.31 ± 0.04 at 60 mV (n = 6) and consistently increased upon
membrane depolarization. In inside-out (i/o) patches with symmetrical
KCl solutions, the channel conductance (22.8 ± 0.8 pS;
n = 10) was similar as in the c/a configuration.
Substitution of the majority of Cl
with gluconate from
KCl solution in the pipette and bath did not significantly alter
reversal potential (Erev) or the channel conductance (19.7 ± 1.1 pS in asymmetrical potassium gluconate, n = 4; 21.4 ± 0.5 pS in symmetrical potassium
gluconate, n = 3). Experiments with 10-fold lower KCl
concentration in bath solution in i/o patches shifted
Erev to near the Erev of
K+. The estimated permeability of K+ vs.
Cl
was over 10, and the conductance was 13.4 ± 0.1 pS (n = 3). The channel did not discriminate between
K+ and Na+, as evidenced by a lack of a shift
in the Erev with different K+ and
Na+ concentration solutions in i/o patches
(n = 3). The current studies demonstrate the presence
of cation channels in the apical membrane of native OMCDi
cells that could participate in K+ secretion or
Na+ absorption.
collecting duct; hydrogen-potassium-adenosinetriphosphatase; potassium channel; sodium channel; patch-clamp recording; inner stripe of the outer medullary collecting duct
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INTRODUCTION |
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THE OUTER MEDULLARY COLLECTING duct of the inner stripe (OMCDi) is a major renal segment for luminal fluid acidification (15, 29) and exhibits large rates of proton secretion due to H+-ATPase and H+-K+-ATPase (34). Although this segment actively reabsorbed K+ when the animal was fed a K+-restricted diet (K+ restriction; see Refs. 30 and 31), the OMCDi had little net K+ transport when the animal was fed a normal K+-containing diet (K+ replete; see Refs. 4, 25, and 30). In addition, either luminal K+ removal or luminal application of Ba2+ inhibited acidification in the OMCDi of K+-replete rabbits (2). These observations suggest that luminal K+, which is reabsorbed via H+-K+-ATPase, recycles back to the lumen through K+ exit pathways under K+-replete circumstances.
However, cation channel conductances have never been directly demonstrated in the apical membrane of the native OMCDi. Although a whole cell K+ conductance was observed in primary culture of rabbit OMCDi cells (23) and a cation channel mRNA was detected in the mouse outer medullary collecting duct (OMCD; see Ref. 6), the contribution of the channel conductance from the apical or basolateral membrane was not detailed.
The purpose of the present study was to examine directly whether
K+-permeable ion channels are present at the apical
membrane of the native OMCDi. Using cell-attached patch and
inside-out patch configurations, we detected single channel
conductances on the apical membrane of the native OMCDi
under K+-replete circumstances. The primary channel we
observed had an increased channel open probability
(Po) when the patched membrane was depolarized,
a high permeability of K+ over Cl, and
approximately the same permeability to Na+ as to
K+. Determination and characterization of this cation
channel in the apical membrane of the native OMCDi cells
extend our previous observations and help us to better understand ion
regulation in the acidification process.
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METHODS |
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Cell preparations. The dissection of OMCD was similar as described previously (2, 30, 31). In brief, New Zealand White female rabbits (1.0-1.8 kg) were fed a normal-K+ diet and were allowed free access to tap water. The rabbits were decapitated, and one kidney was quickly removed, sliced into 1- to 2-mm slices, and placed in chilled Ringer solution (<10°C) that contained (in mM) 135 NaCl, 5 KCl, 1.5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES (pH 7.4 with NaOH). Isolation of single OMCD tubules from those slices was carried out in the same solution. The inner border of the OMCDi was defined as the transition of the white medulla into the pink medulla, and the segment of the OMCDi was chosen from those directly adjacent to thin descending limbs and thick ascending limbs of Henle's loop. In the case of the outer stripe of the OMCD (OMCDo), the outer border of the segment was defined as the transition of the brown cortex into the pink medulla.
The microdissection of the OMCD was much harder than that of the cortical collecting duct (CCD), and most of the dissection procedures were completed under a dissection microscope with up to ×40 amplification (M32; Wild, Heerbrugg, Switzerland). The native tubules were manually slit open by a fine needle or a dissection probe (500135; World Precision Instruments, Sarasota, FL), and then the opened area was extended by a pair of fine forceps. The lumen-opened tubule was placed on a small glass coverslip coated with tissue adhesive (Cell-Tak; Collaborative Biomedical Products, Bedford, MA), which was then transferred to a perfusion chamber (area ~0.75 cm2, volume ~0.5 ml) for patch-clamp recording. The tubule was continuously perfused at room temperature (~20°C). Figure 1 shows a typical OMCDi preparation with the apical membrane facing up.
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Single channel recording and solutions. An Axopatch 200B amplifier with a DigiData 1200 interface (Axon Instruments, Foster City, CA) connected to a 166-MHz Pentium computer (Optiplex GXi; Dell Computer, Round Rock, TX) was used for all recordings. Fetchex software (pClamp 6.0.4; Axon Instruments) was used for data collection. Single channel currents were sampled at 10 kHz, filtered at 2 kHz, and stored on the computer hard disk and on a digital videotape recorder (500C videotape recorder with 3000A PCM recording adaptor; Vetter Digital, Rebersburg, PA) for further analysis.
Patch pipettes were pulled from borosilicate capillary glass using a micropipette puller (PP-83; Narishige International, East Meadow, NY) and fire polished using a microforge (MF-83; Narishige International); the pipettes typically had tip resistance between 5 and 10 MData analysis.
Single channel analysis was performed on records obtained from patches
with seal resistance >10 G. Fetchan and pSTAT software (pClamp
6.0.4; Axon Instruments) were used for calculating the mean channel
current amplitude and for estimating channel Po. The threshold of current amplitude between the two current levels was
manually set. Because most patches contained more than one active
channel and the total number of channels within a patch could not be
determined, Po was used to describe the channel
open activity (or to estimate the open activity from total number of channels in the patch, if NPo is used)
Po = [ (n · tn)/T]/N
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RESULTS |
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Cell-attached patch studies. To examine whether single ion channel conductances exist in the apical membrane of the OMCDi, we first used the cell-attached patch-clamp technique. A high-KCl bath solution was used in these experiments to depolarize the cell membrane potential. With the use of this approach, the voltage across the patch membrane could be determined by the command potential in the patch pipette. In 268 patches when KCl was in the bath and pipette solutions, we observed 50 patches with single channel activity. Figure 2 presents current traces of spontaneous channel activity recorded from an OMCDi cell at different membrane potentials. The channel activity was also detected in the apical membrane of the OMCDo (8 of 35 patches) and the OMCD (the gray area between the OMCDo and the OMCDi; 7 of 38 patches). Because the single channel data among the segments did not show a distinguishable difference, we have grouped the cells together for data analysis.
The channel opening was variable in each experiment as Po varied between 0.03 and 0.1 at
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Inside-out patch studies. When inside-out patches were formed from these cells, >60% of the cells (23 of 37) could maintain the channel activity for a number of minutes. Figure 4B shows the i-V curve from excised patches when KCl was present in the pipette and bath solutions. The slope conductance was 22.8 ± 0.8 pS (n = 10), which is similar to that in the cell-attached configuration.
Ion selectivity studies.
We carried out experiments in the inside-out patch configuration to
clarify the ion selectivity of the channel observed in the OMCD cells.
First, to distinguish cationic current from an anionic one, we replaced
all but 10 mM KCl in the pipette solution with potassium gluconate
[i.e., Cl concentration ([Cl
]) was
altered from ~140 to ~10 mM]. When KCl solution was present in the
bath, similar channel activity was observed in cell-attached patches
(data not shown) and in inside-out patches (Fig.
5A). When the bath solution
was changed from KCl to potassium gluconate, the channel activity was
unaffected. Because K+ concentration ([K+])
was much greater than [Cl
], both in the pipette
solution and in the bath solution, these data suggest that the current
conducted through the recording channels was mainly carried by
K+.
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Cation selectivity studies.
The next set of experiments tested the cation selectivity of the single
channel conductance in this segment. In inside-out configuration with
KCl solution in the pipette, when the bath solution was switched from
KCl solution to NaCl solution, only a very small shift in
Erev to positive potential occurred (~2.7 mV;
n = 3; Fig. 8). The
relative permeability of this channel to Na+ over
K+ is ~0.9 or 1:1.1. The channel conductance was
21.3 ± 1.5 and 21.6 ± 2.3 pS in KCl/KCl solution and in
KCl/NaCl solution, respectively (paired, no significant difference;
n = 3). These data suggest that this channel could
conduct Na+ as well as K+ under the same
recording conditions. A similar i-V curve was obtained with a slope conductance of 22.7 ± 0.9 pS
(n = 5) in the inside-out configuration with NaCl in
the pipette solution and KCl in the bath solution (data not shown).
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Other observations. Besides this most frequently observed 23-pS channel current, other ionic unitary current levels were also observed. Among them, one exhibited a relative small channel conductance of ~10 pS (n = 7) and had a relative linear i-V relationship. The other two were outward rectified with chord conductance (inward/outward) of 16/50 pS (n = 11) and of 41/67 pS (n = 3). All of the conductances were measured in the cell-attached configuration with KCl solution in the pipette and in the bath. Our observations indicate that the 16/50 pS channel was consistent with a cation channel (35). Because these channels were infrequently observed, their characteristics were unable to be explored in detail. It is not clear if their low occurrences were due to either the low density of the channel or the inactive state of the channel.
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DISCUSSION |
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The present study has demonstrated for the first time that the apical membrane of the native OMCDi cells contains a 23-pS nonselective cation channel (see Fig. 2). The spontaneous activity of this cation channel was also detected in the apical membrane of the OMCDo. The channel had a wide range of Po, and membrane depolarization increased Po (see Fig. 3B). The renal medulla is the only tissue in which extracellular osmolarity exceeds that of systemic plasma in mammals. The lumen [K+] in the outer medulla varies with dietary K+ content, and the degree of antidiuresis and may exceed 50 mM. Although the role for voltage-dependent cation channels in the OMCDi is unknown, given the condition of such high lumen K+, the membrane potential of OMCDi cells should be depolarized to a certain degree, which may facilitate the channel opening.
The i-V curve of the 23-pS channel is almost linear in both cell-attached and in inside-out patch configurations (see Fig. 4). The rectification of the inward-rectifier K+ channel is caused by both the block of the outward current by cytoplasmic Mg2+ and by intrinsic channel gating (19). In the present study, the pipette and bath solutions always had 1 mM Mg2+ present, and cytoplasmic Mg2+ did not appear to block the outward current.
The channel is selective for K+ over Cl.
Paired experiments in inside-out patches showed that, when most of the
Cl
in the bath (and in the pipette) was replaced by
gluconate, channel current and conductance were not significantly
changed (see Figs. 5A and 6), but, when most of the
K+ in the bath was replaced by TEA, it failed to show
outward current (see Fig. 5B). These data indicate that
K+ was the contributive ion for the channel current. The
estimated selectivity of the 23-pS channel for K+ over
Cl
was ~11 to 30 times in inside-out patches (see Fig.
7). This estimation of selectivity using the GHK equation was mainly
based on measured Erev under the condition that
solutions contained both K+ and Cl
. The
possible effect of a small portion of Cl
permeability
cannot be excluded.
This study also shows that the channel could pass both of the monovalent cations K+ and Na+ (see Fig. 8). A selective Na+ conductance has not been detected in the OMCDi segment by microperfusion and intracellular recording studies in rabbits (9, 17). It is also reported that, in whole cell patch-clamp studies of cultured OMCDi cells, a 10-fold change in the bathing solution [K+] caused a membrane potential shift, but a 10-fold change in Na+ had no effect (23), which indicates only the presence of a K+ conductance. The differences could be due to the recording configuration (i.e., single channel current vs. whole cell macroscopic current) and the cell preparation (i.e., native cells vs. cultured cells).
In our previous microperfusion study, 2 mM Ba2+ inhibited bicarbonate absorption and decreased transepithelial voltage in perfused OMCDi (3). In the whole cell patch-clamp study of cultured OMCDi, 1 mM Ba2+ did not alter the cell membrane conductance, and an inhibitory effect was seen only when the concentration was 10-fold greater (23). Ciampolillo et al. (6) demonstrated the presence of mRNA for a 28-pS cation channel in the mouse OMCD. As shown by patch-clamp studies in mouse inner medullary collecting duct (IMCD) cells in culture, this 28-pS channel does not discriminate between Na+ and K+ and does not alter channel activity by voltages, Ba2+, TEA, and bath pH changes (13). Studies from the IMCD cell line, mIMCD-3 cells, also showed a 24-pS nonselective cation channel that was activated by a negative suction in the pipette (21). This channel was modulated by bath Ca2+ in excised patches but did not appear to be sensitive to Ba2+ because the inhibitory effect of Ba2+ on channel activity was observed only in very high concentrations. Although the channel described in the present study may not share all of the properties with channels described in the apical membrane of mouse IMCD (13, 21) and mouse OMCD (6), the similarity of both K+ and Na+ permeability in these channels would suggest that, in the medullary collecting duct, such channels constitute a general mechanism for K+ and Na+ regulation.
The OMCDo has been shown to reabsorb Na+ and to secrete K+ but at rates that are less than that in the CCD (24, 26, 32). Although it is not clear whether the OMCDi has the same ability to secrete K+ and to reabsorb Na+ under certain conditions, the presence of cation channels in this segment suggests that this possibility exists.
Nonselective cation channels (with similar permeability for monovalent cations Na+ and K+) have also been found in various CCD cells (1, 10, 12, 14, 16). Most of these channels have a linear i-V relationship with slope conductance of 20-30 pS and have an increased channel activity at depolarized voltages. Such channels have similarities with the channels found in the native OMCDi cells.
It is clear from immunohistochemistry and electron microscopic studies that principal cells and intercalated cells exist in the rabbit OMCDi (27, 33). However, our current experiments under light microscopic observations, including the use of Hoffman modulation contrast optics, could not identify the cell type being patched. In contrast to the CCD, in which "hexagonal" cells and "circular" cells are clearly observed (20, 22, 35), most cells of the OMCDi observed using Hoffman modulation contrast optics exhibit irregular shapes (Fig. 1B). Nevertheless, we observed detectable ionic channel activity in ~20% of the patches that were investigated, a percentage that is similar to the percentage of intercalated cells in this segment (8, 11, 33). Further studies are required to specifically identify the cell types that have cation channel activity.
It is known that intercalated cells have a higher rate of H+ secretion by H+-K+-ATPase than principal cells (28, 29) and thus may require a pathway to recycle K+ back from these cells to the lumen. For example, if the apical membrane H+-K+-ATPase absorbs K+ in exchange for H+ (or H3O+), then K+ must either exit basolaterally (in which case K+ reabsorption would occur) or exit apically (in which case there would be no net K+ reabsorption). Previous studies have shown that the OMCDi has little net K+ reabsorption in K+-replete rabbits (4, 25, 30). Our current data suggest that the renal H+-K+-ATPase may function in parallel with an apical K+-permeable channel in intercalated cells of the OMCDi.
In summary, we have successfully prepared the apical membrane of the native OMCDi to directly examine single channel activity. The current study demonstrates the presence and biophysical properties of cation channels in a subpopulation of cells in this segment. We speculate that these channels could provide K+ recycling during proton secretion by H+-K+- ATPases in the K+-replete condition. However, the exact physiological role of these channels in Na+ absorption and K+ secretion needs to be explored in future studies.
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ACKNOWLEDGEMENTS |
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We thank Jeanette Lynch, Lance Parker, and Robin Moudy for technical support, Dr. Jeff Martin for interaction in the early experiments, and Dr. Kirsten Madsen for use of key equipment during this study and the staff of the Medical Media at the Veterans Affairs Medical Center for photographic processing.
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FOOTNOTES |
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Part of this work was presented in abstract form at the American Society of Nephrology 31st and 32nd annual meetings held in Philadelphia, PA, October 25-28, 1998, and Miami Beach, FL, November 5-8, 1999, respectively.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-49750 and by the Medical Research Service of the Department of Veterans Affairs.
Address for reprint requests and other correspondence: S.-L. Xia, Div. of Nephrology, Hypertension, and Transplantation, P.O. Box 100224, Univ. of Florida, Gainesville, FL 32610-0224 (E-mail: xiasl{at}ufl.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.
Received 26 June 2000; accepted in final form 18 December 2000.
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