1 Division of Pediatric Nephrology, Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029-6574; 2 Renal Division, Department of Medicine, University of Pennsylvania, Philadelphia 19104-6144; and 3 Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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ABSTRACT |
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K+ secretion by the
cortical collecting duct (CCD) is stimulated at high flow rates.
Patch-clamp analysis has identified a small-conductance secretory
K+ (SK) and a high-conductance Ca2+-activated
K+ (maxi-K) channel in the apical membrane of the CCD. The
SK channel, encoded by ROMK, is believed to mediate baseline
K+ secretion. The role of the stretch- and
Ca2+-activated maxi-K channel is still uncertain. The
purpose of this study was to identify the K+ channel
mediating flow-dependent K+ secretion in the CCD. Segments
isolated from New Zealand White rabbits were microperfused in the
absence and presence of luminal tetraethylammonium (TEA) or
charybdotoxin, both inhibitors of maxi-K but not SK channels, or
apamin, an inhibitor of small-conductance maxi-K+ channels.
Net K+ secretion and Na+ absorption were
measured at varying flow rates. In the absence of TEA, net
K+ secretion increased from 8.3 ± 1.0 to 23.4 ± 4.7 pmol · min1 · mm
1
(P < 0.03) as the tubular flow rate was increased from
0.5 to 6 nl · min
1 · mm
1.
Flow stimulation of net K+ secretion was blocked by luminal
TEA (8.2 ± 1.2 vs. 9.9 ± 2.7 pmol · min
1 · mm
1 at 0.6 and 6 nl · min
1 · mm
1 flow
rates, respectively) or charybdotoxin (6.8 ± 1.6 vs. 8.3 ± 1.6 pmol · min
1 · mm
1 at 1 and
4 nl · min
1 · mm
1 flow
rates, respectively) but not by apamin. These results suggest that
flow-dependent K+ secretion is mediated by a maxi-K
channel, whereas baseline K+ secretion occurs through a
TEA- and charybdotoxin-insensitive SK (ROMK) channel.
principal cell; intercalated cell; ROMK; epithelial sodium channels; charybdotoxin; apamin
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INTRODUCTION |
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THE FINAL REGULATION OF URINARY K+ excretion is accomplished in distal nephron segments including the cortical collecting duct (CCD) (5, 12, 13, 31, 41). The CCD is a heterogeneous epithelium comprising two morphologically and functionally distinct cell populations. Principal cells mediate Na+ absorption and K+ secretion (25, 40, 49), whereas intercalated cells primarily function in H+/HCO3 transport and, under certain conditions, K+ absorption (46, 47). K+ secretion in the CCD requires basolateral Na-K-ATPase-mediated uptake of K+ into the principal cell in exchange for Na+. The high cell K+ concentration and lumen negative voltage within the CCD, generated by conductive apical Na+ entry through epithelial Na+ channels (ENaCs) and its electrogenic basolateral extrusion, favor the passive diffusion of cell K+ into the luminal fluid through apical K+-selective channels (10). The magnitude of K+ secretion is determined by its electrochemical gradient and by the permeability of the membrane to K+ (10).
Patch-clamp analysis has identified two types of apical K+ channels in the rat and rabbit CCD. The prevalence of the apical small-conductance K+ (SK) channel, its ability to conduct both K+ and Rb+, and its high open probability (Po) at the resting membrane potential (7, 10, 43, 57) suggest that this channel most likely mediates K+ secretion under baseline conditions. In contrast, the high-conductance Ca2+-activated K+ (maxi-K) channel is rarely open at physiological membrane potentials but can be activated by membrane depolarization, elevation of intracellular Ca2+ concentration ([Ca2+]i), membrane stretch, or hyposmotic stress (6, 11, 18, 22, 38, 51-53). These observations have led to the speculation that the maxi-K channel, considered not to play a major role in baseline K+ secretion in the CCD, functions in cell volume regulation (9, 18) and/or flow-mediated K+ secretion (38, 53). Although the SK channel is present solely in principal cells within the CCD, conducting maxi-K channels have been identified in both principal and intercalated cells in this segment (38, 43). The density of maxi-K channels in intercalated cells exceeds that detected in principal cells (38).
It is well established that high distal tubular flow rates stimulate net K+ secretion in the distal nephron and CCD (5, 12, 13, 23, 30, 42) and urinary K+ excretion (30). This response reflects, at least in part, an increase in delivery to and reabsorption of Na+ by principal cells (10, 44), which, in turn, increases the driving force for passive K+ efflux across the apical membrane. The SK channel has been considered to be the primary route allowing cell K+ to diffuse into the lumen down its favorable electrochemical gradient. The possibility that high urinary flow rates and hydrostatic pressure alter [Ca2+]i or the membrane stretch to which renal epithelial cells are exposed, thereby stimulating apical stretch- and Ca2+-activated maxi-K channels, has not been directly examined in the CCD.
The purpose of the present study was to test the hypothesis that stretch- and Ca2+-activated maxi-K channels mediate flow-stimulated K+ secretion in the CCD. To this end, we sought to 1) examine the effect of tetraethylammonium (TEA) and charybdotoxin, inhibitors of the maxi-K (14, 38, 45, 53) but not the SK channel (7, 53, 57), on flow-stimulated net K+ secretion in rabbit CCDs microperfused in vitro and 2) determine whether immunodetectable maxi-K channels are localized to the apical membrane of these specific nephron segments by using channel-specific antibodies.
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METHODS |
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Isolation of single tubules. Adult female New Zealand White rabbits, obtained from Covance (Denver, PA), were housed in our animal care facility and given water and standard chow ad libitum. Animals were killed by intravenous injection of pentobarbital (100 mg/kg). The kidneys were removed, sliced into 2-mm coronal sections, and placed into a dish containing chilled dissection solution containing (in mM) 140 NaCl, 2.5 K2HPO4, 2 CaCl2, 1.2 MgSO4, 5.5 D-glucose, 1 Na3 citrate, 4 lactic acid, and 6 L-alanine, pH 7.4, 290 ± 2 mosmol/kgH2O. A single tubule was studied from each animal.
Each isolated tubule was transferred immediately to a temperature- and O2/CO2-controlled specimen chamber, mounted on concentric glass pipettes, and perfused at 37°C as previously described (41). Tubules were initially perfused and bathed in Burg's solution that resembled the dissection solution except that 25 mM NaCl was replaced by NaHCO3 (41). During the 60-min equilibration period and thereafter, the perfusion chamber was continuously suffused with a gas mixture of 95% O2-5% CO2 to maintain pH of the Burg's solution at 7.4 at 37°C. The bathing solution was continuously exchanged at a rate of 0.3 ml/min by using a peristaltic pump.Measurement of cation fluxes.
Transport measurements in isolated tubules were performed in the
absence of transepithelial osmotic gradients; thus water transport was
assumed to be zero. Samples of tubular fluid were collected under
water-saturated light mineral oil by timed filling of a precalibrated
20-nl volumetric constriction pipette. The flow rate was varied from
0.5 to 6 nl · min1 · mm
1 by
adjusting the height of a perfusate reservoir. The K+ (and
Na+) concentration of perfusate and collected tubular fluid
was determined by helium glow photometry, and rates of net cation
transport (in pmol · min
1 · mm
1 tubular
length) were calculated, as previously described (41).
Western blotting of maxi-K channel protein in kidney.
Mouse kidneys were homogenized in a buffer containing 250 mM sucrose,
10 mM triethanolamine, pH 7.6, and supplemented with protease
inhibitors {Protease Inhibitor Cocktail Set III, final concentration
1 mM [4-(2-aminoethyl)benzenesulfonylfluoride], 0.8 µM aprotinin,
50 µM bestatin, 15 µM E-64, 20 µM leupeptin, and 10 µM
pepstatin A, Calbiochem, San Diego, CA}. Aliquots of protein (100 µg) were subject to 3-15% SDS-PAGE and transferred to an
Immobilon-NC membrane (Millipore, Waltham, MA). Blots were probed with
a commercially available rabbit antibody directed against the
-subunit of the maxi-K channel (1.5 µg/ml, Alomone Labs,
Jerusalem, Israel) or with nonimmune rabbit IgG (1.5 µg/ml, Jackson
ImmunoResearch Labs, West Grove, PA). Bound antibody was detected
following incubation with a 1:2,500 dilution of horseradish peroxidase-conjugated goat anti-rabbit IgG (Kirkegaard and Perry Laboratories, Gaithersburg, MD) by chemiluminescence (Western Blot
Chemiluminescence Reagent Plus, NEN, Boston, MA).
Indirect immunofluorescence localization of maxi-K channels in the kidney. Because available antibodies directed against the maxi-K channel are raised in rabbit and can thus not be used to immunolocalize the protein in rabbit tissue, the following studies were performed in mouse kidney. To the extent that expression patterns of immunodetectable and functional ROMK are similar between rabbit and rat (7, 33, 43, 60), we considered it likely that the abundance and localization of maxi-K channels would also be similar among the various rodent species.
Adult mouse (CD-1 strain) kidney was sliced into sagittal sections and fixed in 4% paraformaldehyde prepared in 5% sucrose in PBS for 1 h. Thereafter, the tissue was incubated in 50 mM NH4Cl in 5% sucrose/PBS for 10 min to quench nuclear staining. After washing twice with 5% sucrose/PBS, the tissue was immersed in graded sucrose/PBS solutions to a final sucrose concentration of 2.3 M for cryoprotection. Blocks of tissue were embedded in OCT-compound (Sakura Finetek, Torrance, CA), diluted 1:2 with 20% sucrose, frozen, and stored atReagents. TEA chloride, the scorpion toxin charybdotoxin (99% purity), and the bee venom apamin (99% purity) were obtained from Sigma (St. Louis, MO). TEA, charybdotoxin, and apamin were diluted to final concentrations of 5 mM and 10 and 100 nM, respectively, in the luminal perfusate.
Statistics. All results are expressed as means ± SE; n equals the number of tubules or animals. Regression lines were constructed by the method of least squares. Comparisons were made by paired and unpaired t-tests as appropriate. Significance was asserted if P < 0.05.
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RESULTS |
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Effect of TEA on flow-stimulated net K+ secretion.
As we (41) and others (5, 50) have previously
reported, net K+ secretion increased significantly from
8.3 ± 1.0 to 23.4 ± 4.7 pmol · min1 · mm
1
(P < 0.03 by linear regression analysis;
n = 6-11 CCDs at each flow rate) as the tubular
flow rate increased from 0.5 ± 0.1 to 6.3 ± 0.9 nl · min
1 · mm
1 (Fig.
1, solid bars). There was no significant
change in Vte as flow was increased between
these flow rates [
9.0 ± 0.9 to
5.0 ± 1.8 mV;
P = not significant (NS)]. Note that the physiological flow rate for the distal nephron of the rabbit averages ~1
nl · min
1 · mm
1
(3).
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Effect of apamin and charybdotoxin on flow-stimulated net
K+ secretion.
Apamin inhibits a widely expressed, small-conductance maxi-K channel
that is TEA insensitive (35) but does not inhibit the TEA-sensitive maxi-K channel in the CCD when studied at the
single-channel level (45). Luminal perfusion with 100 nM
apamin did not significantly affect the rates of net K+
secretion (Fig. 3) or Na+
absorption (Fig. 4) at a slow flow rate
of 0.8 nl · min1 · mm
1. A
fourfold increase in luminal flow rate stimulated both net K+ secretion (from 4.8 ± 0.8 to 13.1 ± 1.3 pmol · min
1 · mm
1;
P < 0.001) (Fig. 3) and net Na+ absorption
(from 17.8 ± 1.8 to 72.4 ± 8.6 pmol · min
1 · mm
1;
P < 0.01) (Fig. 4) in eight apamin-treated CCDs. The
rates of net K+ secretion and Na+ absorption
measured at high flow rates in the presence of apamin did not differ
from those measured in a flow rate-matched group of CCDs perfused with
Burg's solution alone (18.7 ± 3.6 and 57.3 ± 9.3 pmol · min
1 · mm
1,
respectively, in 11 CCDs perfused at a mean rate of 4 nl · min
1 · mm
1;
P > 0.2).
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Western analysis of maxi-K channel protein in kidney homogenate.
An immunoblot of whole mouse kidney lysate was performed to
characterize the anti-maxi-K channel antibody. Polypeptides with apparent molecular masses of ~70 and 42 kDa were recognized by the
antibody but not by nonimmune IgG (Fig.
5). The 70-kDa polypeptide corresponds to
the reported molecular mass of the -subunit of the maxi-K channel
(24). The 42-kDa polypeptide may represent a proteolytic
fragment of the channel protein.
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Immunolocalization of maxi-K channels in the kidney.
Double immunofluorescence labeling of cryosections of mouse cortex with
antibodies directed against the -subunit of the maxi-K channel and
AQP2 revealed colocalization along the apical membranes of a discrete
group of tubules, presumably collecting ducts (Fig. 6). Patch-clamp analysis has identified
functional maxi-K channels in both principal (28, 38, 43,
57) and intercalated (38) cells in the CCD; thus we
did not attempt to discern the identity of collecting duct cells
expressing the antigen. Functional apical maxi-K channels have been
identified not only in the CCD but also in the thick ascending limb of
the loop of Henle (TALH) (15, 34, 56). Consistent with the
latter observation, prominent labeling with the anti-maxi-K channel
antibody was detected along the apical membranes of collapsed TALHs
(Fig. 6).
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DISCUSSION |
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Flow-stimulated K+ secretion in the CCD has been proposed to arise, in part, from increased delivery to and reabsorption of luminal Na+ from the tubular lumen, a process that enhances the lumen negative potential and rate of basolateral K+ uptake, thereby increasing the driving force for passive K+ efflux across the apical membrane. Whereas the SK channel has been considered to represent the predominant channel for K+ secretion in the CCD, others have suggested that high flow rates increase luminal hydrostatic pressure and activate maxi-K channels (10, 38, 53). In support of this argument was the report by Taniguchi and Imai (53) that the flow-dependent increase in apical K+ conductance in the isolated perfused rabbit connecting tubule, estimated by measuring the deflection of Vte in response to a step increase in luminal K+ concentration, was inhibited by luminal charybdotoxin and thus likely mediated by a maxi-K channel.
To directly examine the contribution of the maxi-K channel to
flow-stimulated K+ secretion in the CCD, we exploited the
sensitivity of the maxi-K channel to low concentrations of luminal TEA
and charybdotoxin (6, 14, 38, 45, 53). Neither the SK
channel (53, 57) nor ROMK, a cDNA encoding an
ATP-regulated K+ channel considered to represent the major
functional subunit of the SK channel (19, 59), is
inhibited by these blockers. As shown in Figs. 1 and 3, luminal
perfusion of isolated CCDs with either TEA or charybdotoxin
significantly inhibited flow-dependent but not baseline net
K+ secretion. These data strongly suggest that the maxi-K
channel mediates flow-dependent K+ secretion in the CCD.
The absence of the effect of TEA and charybdotoxin on K+
secretion in CCDs perfused at physiological flow rates (~1-2 nl · min1 · mm
1) is
compatible with the proposed role of the SK channel in mediating baseline K+ secretion.
We acknowledge that other as yet unidentified TEA- and charybdotoxin-sensitive K+ channels in the CCD that contribute to K+ secretion may exist. Indeed, a growing number of cloned K+ channels have been identified at the molecular level in the CCD (4, 27, 37, 39). Among these is TWIK-1, a member of the two-pore-domain family of K+ channels (4), which has been immunolocalized to the apical membranes of intercalated cells (4). Whereas the localization of TWIK-1 suggests that it may contribute to K+ secretion, the low sensitivity of this channel to TEA (4, 27) leads us to suspect that TWIK-1 does not mediate flow-stimulated K+ secretion.
The maxi-K channel has not been considered to play a major role in K+ secretion in the CCD. When studied by patch-clamp analysis in the cell-attached configuration, this channel is characterized by a single-channel conductance of ~100 pS, a low density, and low Po (38, 43). We consider that our detection of a maxi-K channel-mediated K+ secretory flux may reflect, in part, technical differences between the conditions employed for electrophysiological analysis and those utilized in this in vitro microperfusion study. Specifically, in the present study, CCDs were perfused at 37°C in the presence of HCO3/CO2, conditions that will allow segments to transport H+/HCO3, which may, in turn, influence K+ channel activity (9, 38). Additionally, the circumferential stretch and increase in hydrostatic pressure to which CCDs are exposed when microperfused at fast flow rates, likely leading to concave deformation of the apical membrane, differ from the "convex" apical membrane deformation experienced by cells in split-open CCDs prepared for patch-clamp analysis in the cell-attached or inside-out modes. A differential activation of channel activity by convex compared with concave curvature of the membrane has been reported for the mechanosensitive TWIK-related arachidonic acid-stimulated K+ channel, TRAAK (29).
Among the likely signals mediating the activation of the maxi-K channel at high flow rates are membrane depolarization, elevation of [Ca2+]i, and/or membrane stretch. Fast tubular flow rates stimulate net Na+ absorption in the CCD in the presence (Fig. 2) and absence (44) of K+ secretion and would be expected to result in membrane depolarization (17). We have recently shown that an acute increase in luminal fluid flow rate transiently increases [Ca2+]i from ~100 to 250 nM in both principal and intercalated cells in the rabbit CCD (58). Although this peak elevation in [Ca2+]i is within range of that considered necessary to activate maxi-K channels in the CCD (>100 nM) (38) and connecting tubule (500 nM) (53), the concentration of Ca2+ achieved in the immediate vicinity of the channel may be much greater. A flow-dependent increase in [Ca2+]i may reflect inhibition of basolateral Na+/Ca2+ exchange as cell Na+ entry increases at high flow rates (1, 2, 8). Alternatively, an increase in luminal fluid flow rate may stimulate apical Ca2+ entry through stretch-activated Ca2+-permeable channels as has been proposed to occur in the isolated perfused rabbit connecting tubule (54). Note that membrane depolarization and Ca2+ can independently activate maxi-K channels and may lead to additive effects (20, 21).
It is well established that the apical maxi-K channel in the distal nephron is stretch activated. Application of negative pressure to the patch-clamp pipette increases the mean number of open channels in apical cell-attached patches of TALH (52), connecting tubule (53), and CCD (38). The relationship between membrane stretch and [Ca2+]i in maxi-K activation has been explored by patch-clamp analysis in both the cell-attached and excised inside-out configuration after chelation of free Ca2+ with EGTA added to either the pipette or bath solutions, respectively. Whereas Pacha et al. (38) showed that the mechanosensitivity of the maxi-K channel in rat CCD was retained under both of these conditions, suggesting that stretch activation of the maxi-K channel was not mediated by an increase in [Ca2+]i, Taniguchi and Imai (53) reported that the maxi-K channel in rabbit connecting tubule was not stretch activated in the absence of ambient Ca2+. Whether the discrepant results reflect interspecies differences in inhibitor sensitivity or the presence of different isoforms of the maxi-K channel in CCD and connecting tubule remains to be determined.
Additional support for cell stretch as a signal for apical channel
activation in CCDs perfused at high flow rates is suggested by our
recent observation that amiloride-sensitive Na+ currents in
oocytes expressing -,
-, and
-mENaC increased sixfold in
response to increasing the rate of flow of a
Na+/K+ chloride bath, superfusing the oocytes
from 0 to 6 ml/min, a maneuver that presumably results in some
mechanical deformation of the oocyte membrane (44). In
contrast, Ba2+-sensitive K+ currents in oocytes
injected with ROMK1 increased only twofold in response to an identical
maneuver (44).
The presence of immunodetectable maxi-K channel protein along the
apical membranes of both CCD and TALH (Fig. 6) is consistent with
functional expression of a ~70- to 100-pS K+ channel in
both of these nephron segments (15, 34, 56). Two subunits
of the maxi-K channel have been cloned. Coexpression of the
pore-forming - and regulatory
-subunits of the maxi-K channel in
Xenopus laevis oocytes increases the Ca2+,
voltage, and charybdotoxin sensitivity of the channel compared with
that observed when the
-subunit is expressed alone (16, 32). Several alternate transcripts of the
-subunit have been reported in different species (26, 36, 55). Two
transcripts of the
-subunit (rbslo 1 and 2) have been
identified in rabbit kidney (36). Rbslo is
expressed in glomeruli, thin limb of Henle, TALH, and cortical and
medullary collecting ducts but is rarely detected in proximal tubule
(36). Whether the identity and abundance of
rbslo transcripts in TALH and CCD are similar remains to be determined.
From a clinical perspective, the proposed role of the maxi-K channel as a K+ secretory channel recruited under conditions of high distal tubular flows may provide a route for urinary K+ excretion in the absence of functional SK (or ROMK) channels. In support of this proposed role are the observations that patients with Bartter's syndrome, associated, in some cases, with loss-of-function mutations in the ROMK gene, have modest hypokalemia (48). Although the hypokalemia may arise from K+ wasting associated with loss of Na-K-2Cl cotransport in the TALH, our data suggest that increased delivery of tubular fluid to the CCD may activate maxi-K channels, thereby augmenting urinary K+ losses.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Shaohu Sheng, Bill Miyawaki, and Lawrence Palmer for insightful discussions, Jim Wade for providing the anti-AQP2 antibody, and Beth Zavilowitz and James Bruns for technical support.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-51391 (T. R. Kleyman) and DK-38470 (L. M. Satlin) and an American Heart Association Grant-in-Aid (L. M. Satlin). An abstract of this work was presented at the Annual Meeting of the American Society of Nephrology, October 2000, Toronto, Ontario, Canada.
Address for reprint requests and other correspondence: L. M. Satlin, Box 1664, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574 (E-mail: lisa.satlin{at}mssm.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 11 October 2000; accepted in final form 10 January 2001.
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