Departments of 1 Pharmacology and 2 Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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ABSTRACT |
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Resting Ca2+ absorption by cortical thick ascending limbs (CALs) is passive and proceeds through the paracellular pathway. In contrast, parathyroid hormone (PTH) stimulates active, transcellular Ca2+ absorption (JCa). The Ca2+-sensing receptor (CaSR) is expressed on serosal membranes of CALs. In the present study, we tested the hypothesis that activation of the CAL CaSR indirectly inhibits passive Ca2+ transport and directly suppresses PTH-induced cellular JCa. To test this theory, we measured JCa and Na absorption (JNa) by single perfused mouse CALs. Net absorption was measured microfluorimetrically in samples collected from tubules perfused and bathed in symmetrical HEPES-buffered solutions or those in which luminal Na+ was reduced from 150 to 50 mM. We first confirmed that Gd3+ activated the CaSR by measuring intracellular Ca2+ concentration ([Ca2+]i) in CALs loaded with fura 2. On stepwise addition of Gd3+ to the bath, [Ca2+]i increased, with a half-maximal rise at 30 µM Gd3+. JCa and transepithelial voltage (Ve,) were measured in symmetrical Na+-containing solutions. PTH increased JCa by 100%, and 30 µM Gd3+ inhibited this effect. Ve was unchanged by either PTH or Gd3+. Similarly, NPS R-467, an organic CaSR agonist, inhibited PTH-stimulated JCa without altering Ve. Neither PTH nor Gd3+ affected JNa. Addition of bumetanide to the luminal perfusate abolished JNa and Ve. These results show that CaSR activation directly inhibited PTH-induced transcellular JCa and that cellular Ca2+ and Na+ transport can be dissociated. To test the effect of CaSR activation on passive paracellular Ca2+ transport, JCa was measured under asymmetrical Na conditions, in which passive Ca2+ transport dominates transepithelial absorption. PTH stimulated JCa by 24% and was suppressed by Gd3+. In this setting, Gd3+ reduced Ve by 32%, indicating that CaSR activation inhibited both transcellular and paracellular Ca2+ transport. We conclude that the CaSR regulates both active transcellular and passive paracellular Ca2+ reabsorption but has no effect on JNa by CALs.
calcium transport; thick ascending limbs; kidney; parathyroid hormone; transepithelial voltage
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INTRODUCTION |
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RENAL CA2+ ABSORPTION PROCEEDS throughout the nephron. The majority of filtered Ca2+ is reclaimed by proximal tubules, where it is absorbed largely by passive transport processes and is not subject to specific hormonal regulation. In contrast, downstream Ca2+ absorption in cortical thick ascending limbs (CALs) is mediated by a combination of active and passive absorption (16), and exclusively by active cellular absorption in distal convoluted tubules (DCTs) (10). Moreover, the CAL and DCT are sites where the PTH and PTH-related peptide receptor (PTH1R) is expressed (36, 45, 55). PTH stimulates active Ca2+ transport in both of these tubule segments (2, 16).
Two early observations suggested that renal Ca2+ absorption is regulated, at least in part, by extracellular Ca2+ itself. First, a prodigious literature testifies to the inhibitory effect of hypercalcemia on renal Ca2+ absorption (39). Some of the attenuation is presumably due to reductions in circulating PTH. However, when Ca2+ was acutely raised in thyroparathyroidectomized rats, tubular Ca2+ absorption clearly diminished and was accompanied by increased urinary Ca2+ excretion (41). Furthermore, Ca2+ infusion inhibited distal Ca2+ absorption without affecting Na+ or K+ transport. Therefore, the inhibitory actions of Ca2+ infusion are not likely to be due to reductions of glomerular ultrafiltration (32). Second, raising extracellular Ca2+ selectively inhibited PTH-stimulated cAMP formation in CALs but not in proximal tubules (49), where PTH1Rs are also expressed. These findings are now attributed to the activation by extracellular Ca2+ of the Ca2+-sensing receptor (CaSR).
The CaSR is prominently expressed in CAL and in DCT, although to a
lesser extent in the latter (44). In CALs, the CaSR is located on basolateral plasma membranes (44). Extensive
studies by Wang et al. (51, 52) established that the CaSR
regulates an apical membrane 70-pS K+ channel that is an
important determinant of the transepithelial voltage
(Ve) in CALs. In CALs, Ve
is normally oriented with the lumen electropositive with respect to the
basolateral surface. Activating the CaSR decreases the K+
current, thereby depolarizing Ve. The reduction
in voltage, in turn, would be expected to result in diminished passive,
paracellular Ca2+ absorption (2). Indeed,
increasing basolateral Ca2+ inhibited net Ca2+
absorption (J,
K+, or Mg2+ transport (12). While
these findings are entirely consistent with the proposed role of the
extracellular CaSR to regulate Ca2+ absorption by CALs, two
relevant issues require further examination. First, in studies by
Desfleurs et al. (12), CaSR activation was achieved by
raising basolateral Ca2+. The CAL, however, is rather
permeable to Ca2+ (3), and elevating
Ca2+ asymmetrically at the serosal surface would be
expected to enhance Ca2+ backflux and result in diminished
J
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MATERIALS AND METHODS |
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Single-tubule microperfusion.
The techniques used for studying Ca2+ absorption by single
in vitro microperfused mouse CALs were similar to those described originally by Burg et al. (6, 7) for isolated rabbit
nephron segments and to those used previously by this laboratory
(16, 17, 19) for the study of transport processes in
segments of mouse CAL. Stated briefly, 25- to 30-day-old (~20 g) male
ICR white mice (Harlan, Indianapolis, IN) were killed by cervical dislocation and rapid exsanguination. All protocols were approved by an
institutional animal care and use committee. The kidneys were removed,
and the cortical thick limbs were dissected freehand, without use of
collagenase or other enzymatic treatment, from coronal sections of
renal cortex immersed in a HEPES-buffered solution containing 5% BSA
and maintained at 4°C (see Table 1 for
composition). After transfer to a Lucite chamber, tubule segments 0.5-1.0 mm in length were connected to concentric glass pipettes, and perfusion was initiated by hydrostatic pressure. The tubules were
perfused at rates of 2-15 nl/min at 25°C; the specific perfusion rate is indicated in each set of experiments and did not vary statistically among groups. Fluid was collected in constant-bore pipettes under water-saturated mineral oil. In the absence of fluid
absorption, the rate of tubule perfusion was calculated from the
collection rate. The peritubular bath flowed at a constant rate of 1 ml/min.
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Perfusion and bathing solutions. The compositions of the various tubular perfusion and bathing solutions are indicated in Table 1. All solutions were adjusted to pH 7.4 and 290 mosmol/kgH2O and were equilibrated with 100% O2. The chamber was bubbled with 100% O2.
Microchemical measurements.
The Ca2+ and Na+ concentrations of 15-nl
samples of perfused and collected tubular fluid were determined by a
fluorimetric procedure based on fluo 3 and sodium green (Molecular
Probes, Eugene, OR), respectively (56) using a NanoFlo
fluorimeter (WPI, Sarasota, FL). Because the rate of net fluid
absorption in thick limbs is indistinguishable from zero,
J1 · cm
1) or sodium
absorption (J
1 · cm
1) was
calculated according to the relationship
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(1) |
Measurement of Ve. Ve (mV) was measured across the proximate end of the perfused tubule by introducing a chlorided silver wire into a side port connected to the axial inner perfusion pipette. The ground loop was formed by a Ag/AgCl wire inserted into the bath and connected to a high-impedance amplifier, and the output was displayed on a digital multimeter.
Intracellular free Ca2+. Intracellular free Ca2+ concentration ([Ca2+]i; nM) was determined in single perfused tubules by incubating dissected tubule fragments with 10 µM fura 2-AM for 1 h at 18°C as previously performed (1). The tubule was then transferred to the stage of an inverted microscope and connected to concentric holding and perfusion pipettes as described above. The microscope was fitted with an InCyt Im2 imaging system (Intracellular Imaging, Cincinnati, OH) through the epifluorescence port. Eight to ten cytoplasmic fields were identified along the length of the tubule in which [Ca2+]i was continuously monitored. Calibration was performed using known standards.
Materials. Bovine PTH(1-84) [bPTH(1-84)] was obtained through the National Hormone and Pituitary Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, MD). Fura 2-AM, fluo 3, sodium green, and Ca2+ calibration standards were purchased from Molecular Probes. NPS R-467 was obtained from NPS Pharmaceuticals, Salt Lake City, UT. It was added directly to the peritubular bathing solution at a final concentration of 10 µM. All other reagents were obtained from Sigma and were of the highest analytic grade available.
Statistics.
Data are presented as means ± SE, where n indicates
the number of independent experiments. Effects of experimental
treatments were assessed by paired comparisons within experiments and
reported as the means ± SE of n independent
experiments. Paired results were compared by ANOVA with posttest
repeated measures analyzed by the Bonferroni or Tukey procedure (Instat
3; GraphPad, San Diego, CA). Differences greater than P 0.05 were assumed to be significant.
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RESULTS |
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Activation of CaSR by Gd3+ in single CALs. Pilot experiments were conducted to characterize the effects and kinetic parameters of Gd3+ action on the CaSR. Single mouse CALs were dissected and perfused as described in MATERIALS AND METHODS. However, in this instance, the tubules were loaded with fura 2 and a fluorescence microscope was used that permitted collecting real-time measurements of [Ca2+]i along the length of the perfused segment. Gd3+ was introduced in the serosal bathing solution in a stepwise manner. On addition of 3, 30, or 300 µM Gd3+ to the serosal bathing solution in the presence of 1 mM Ca, [Ca2+]i increased by 50, 80, and 155 nM, respectively. Because half-maximal increases in [Ca2+]i occurred at 30 µM Gd3+, this concentration was used in subsequent studies of the effects of CaSR activation on Ca2+ or Na+ absorption.
We next measured Ca2+ absorption under conditions in which the concentrations of Ca2+ and of Na+ in the perfusate and bath were identical and in the presence of a spontaneous Ve. In this environment, J
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DISCUSSION |
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The experiments described here were intended to determine the action of CaSR activation on PTH-stimulated Ca2+ absorption by the mouse CAL. An earlier study established that elevated basolateral Ca2+ inhibited basal Ca2+ absorption (12). However, the effects of CaSR activation on hormone-stimulated transcellular Ca2+ absorption were not investigated. We now report that CaSR activation with trivalent Gd3+ or with the calcimimetic NPS R-467 inhibits PTH-stimulated active Ca2+ absorption. CaSR activation also suppressed passive paracellular Ca2+ absorption, thereby providing independent confirmation of the findings obtained by Desfleurs et al. (12). The effects of CaSR activation were specific for Ca2+ absorption and had no effect on Na+ transport.
CaSRs are expressed on both CALs and on medullary thick ascending limbs (MALs) (45, 55). Notably, in thick limbs the CaSR is expressed on basolateral membranes, whereas in proximal tubules and collecting ducts the receptor is found on apical plasma membranes (44). Thus it has been presupposed that in CALs the CaSR monitors the Ca2+ composition of peritubular fluid and presumably regulates Ca2+ absorption. PTH receptors have also been localized along the length of the thick ascending limb based on the ability of PTH to stimulate adenylyl cyclase activity (5). In the mouse, PTH receptors were found virtually exclusively in CALs, but not MALs. In two studies (36, 45), PTH receptor mRNA was expressed in rat CAL but not MAL but was found in both CAL and MAL in a third (55). The presence of the CaSR on both CALs and MALs, but of the PTH receptor only in mouse CAL, is consistent with studies showing that hypercalcemia selectively inhibited PTH-stimulated cAMP formation by the CAL, whereas hypercalcemia suppressed vasopressin-induced cAMP accumulation in MALs (49). These findings are also compatible with the observation that hypercalcemia exerts a profound inhibitory action on Ca2+ absorption by thick ascending limbs in the thyroparathyroidectomized rat but exhibited only a minor inhibitory effect on Na+ absorption (41).
Ligands that mimic or potentiate the actions of extracellular Ca2+ on the CaSR are termed calcimimetics. They are grouped into two categories. Type I calcimimetics are full agonists and include Ca2+ and a variety of other inorganic and organic polycations (37). Type II calcimimetics are phenylalkylamine derivatives that allosterically modulate the CaSR. The initial set of experiments described here evaluated the effect of CaSR activation on PTH-dependent Ca2+ absorption. The pharmacology of CaSR activation in thick limbs exhibits substantial species variability. For example, Gd3+, neomycin, and elevated extracellular Ca2+ evoked strong increases in [Ca2+]i in the mouse CAL (40), whereas in the rabbit only Ca2+ exhibited such an effect (12). In the rat, most type I calcimimetics elicited CaSR-mobilized Ca2+ release in the CAL (9, 14). Gd3+ was chosen as the prototype of a non-Ca2+ type I CaSR agonist so as to maintain equal concentrations of Ca2+ at both apical and basolateral surfaces, thereby avoiding a transepithelial Ca2+ gradient that would alter passive Ca2+ diffusion, and because it is the most universal non-Ca2+ CaSR ligand. Pilot studies were performed that identified the concentration of Gd3+ that elicited a half-maximal activation of the CaSR, as reflected by the rise in [Ca2+]i in mouse CAL. The concentration of Gd3+ so determined was 30 µM, consistent with that reported in other tissues (37).
Under symmetrical perfusion and bathing conditions,
J1 · cm
1 and the
average Ve was 5.9 mV (Table 2). Both of these
parameters are consistent with those reported in other studies
(16, 19). Addition of PTH to the serosal bath increased
J
1 · cm
1 without an
accompanying change in Ve. On addition of
Gd3+, J
The inhibitory effects of Gd3+ on PTH-stimulated Ca2+ absorption were reproduced with an unrelated organic compound, NPS R-467, a type II calcimimetic (Table 3). This finding supports the view that the inhibitory effects observed with Gd3+ are likely due to its activation of the CaSR and attendant release of Ca2+ and were not due to blockade of ATP-permeable channels (46), Ca2+-sensitive K+ channels, the nonselective Ca2+-permeable cation channel polycystin-2 (25), the Ca2+-selective Trp3 channel (38), or other nonselective cation channels (15, 54) or mechanosensitive channels (27). It should be noted that although the solutions containing Gd3+ were prepared to a final concentration of 30 µM, the free Gd3+ concentration was likely to be substantially lower. The reason for this is that trivalent phosphate anions in the extracellular bathing solution avidly bind free Gd3+ (8).
To determine whether the inhibitory effect of CaSR activation in the
CAL was specific for Ca2+ transport and to verify the
conclusion that there was no effect on passive driving forces, we
examined the effects of PTH alone or in combination with
Gd3+ on Na+ absorption in the same
extracellular fluid environment as before. In contrast to the action on
Ca2+ absorption, PTH had no discernable effect on
J
The mechanism whereby CaSR activation inhibits PTH-dependent Ca2+ absorption has not been examined. Several possible pathways may be involved. Activation of the CaSR results in G-protein-dependent stimulation of phospholipase C with attendant inositol trisphosphate formation and rapid but transient release of Ca2+ from intracellular stores. Other CaSR signaling pathways, including activation of Gi, phospholipase A2, phospholipase D, and mitogen-activated protein kinase, have been described but are less well characterized (4, 34). Because PTH stimulation of Ca2+ transport in CAL cells and in DCTs requires activation of protein kinase A (20), it is attractive to speculate that the negative regulatory effect of Gi blocks the stimulatory influence on Gs, thereby abrogating the action of PTH.
Because neither PTH nor Gd3+ affected
J activity (26). In this
setting, the stimulatory effect of PTH on Ca2+ entry, which
requires membrane hyperpolarization, is negated and cellular
Ca2+ transport is abolished (24). However, we
have no explanation for the finding that PTH increased
Ve.
The final set of studies examined the influence of CaSR activation on
Ca2+ absorption under conditions in which transepithelial
Ca2+ transport is dominated by its passive movement. This
was accomplished by imposing a salt-dilution voltage across the tubule
by reducing the Na+ concentration of the luminal fluid
(Table 1). In the presence of the high
Na+-to-Cl permselectivity ratio of the
paracellular pathway of the CAL, this strongly enhances the magnitude
of the lumen-positive Ve (3, 28,
30). By reducing luminal Na+ to 50 mM,
Ve increased to 27 mV and was accompanied by a
substantial augmentation of passive Ca2+ absorption (Fig.
3, Table 5) compared with that observed under symmetrical
Na+ conditions (Fig. 1, Table 2). Addition of PTH elicited
only a modest enhancement of J
When the luminal Na+ concentration was reduced to 50 mM but
the serosal bathing solution contained 150 mM Na+ (Table
1), Gd3+ reduced Ve by 30% (Table
5). This effect may have several explanations. The imposition of
asymmetrical external solutions is likely to promote cell swelling with
a variety of compensatory sequelae. Hypotonicity inhibits the
functional activity of the apical
Na+-K+-2Cl cotransporter
(22). The inhibitory effect of Gd3+ may be due
to blockade of swelling-sensitive mechanosensitive channels that are
activated under these conditions (50). However, there may
well be additional or alternative molecular targets of Gd3+
action. Apical membrane K+ current is low under conditions
of symmetrical external Na+, but its activity and
sensitivity to blockade by Gd3+ (52) may be
augmented as part of a regulatory volume decrease. A related
possibility is that dilution of the luminal fluid causes some reduction
in the NaCl concentration within the lateral intercellular space (LIS).
Such a decrease in ionic strength may modify the sensitivity of the
CaSR as described by Quinn et al. (42). However, in a
study of the effect of luminal dilution on dilation of the LIS
(35), an even greater dilution of the luminal fluid (to 70 mosM) than imposed here resulted in a 10% change in the volume of the
LIS. If the magnitude of the change of ionic strength of the fluid in
the paracellular pathway was of the same magnitude, it is unlikely to
have affected the CaSR sensitivity. Finally, the asymmetrical
conditions employed here may directly affect the behavior of
basolateral membrane Cl
channels as shown for such
channels reconstituted in bilayer membranes (43). However,
it is difficult to predict, on the one hand, the effect of asymmetrical
external conditions on intracellular Cl
activity,
especially in view of the finding that trans, i.e., cytosolic, Cl
gates basolateral Cl
channels
derived from MAL but not CALs (53), on the other.
In the context of Ca2+ absorption along the entire length of the thick ascending limb, transport is a combination of passive paracellular movement and active cellular absorption. The latter process would be restricted to those segments and species in which PTH receptors are expressed. Because PTH receptors are generally limited to the CAL, it is likely that the majority of Ca2+ absorption proceeds through a passive mechanism. This is compatible with the view that changes in Ca2+ absorption in thick limbs proceed in parallel with those of Na+. When Na+ absorption by thick limbs is decreased by loop diuretics such as furosemide, the increases in Na+ excretion are accompanied by enhanced Ca2+ excretion. Similarly, in Bartter's syndrome Na+ wasting is attended by conspicuous Ca2+ losses (13, 47). These clinical observations underscore the view that Ca2+ absorption by thick limbs is driven secondarily to that of Na+. By the end of the CAL, the tubular Na+ concentration is markedly reduced, thus resembling the asymmetrical external environment applied here. In this situation, activation of the CaSR would be expected to reduce Ca2+ absorption and contribute to its excretion. Such receptor activation arises during hypercalcemia, in which reduction of renal Ca2+ reabsorption would represent a purposeful compensatory response. The results described herein suggest that CaSR activation would be expected to dampen both passive and active Ca2+ transport, thereby promoting greater Ca2+ excretion in an attempt to restore extracellular Ca2+ to normal levels.
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ACKNOWLEDGEMENTS |
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These studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-54171. NPS R-467 was kindly provided by Dr. Edward F. Nemeth, NPS Pharmaceuticals, Salt Lake City, UT.
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FOOTNOTES |
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Present address of H. I. Motoyama: Dept. of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
Address for reprint requests and other correspondence: P. A. Friedman, Dept. of Pharmacology, Univ. of Pittsburgh School of Medicine, E1347 Biomedical Science Tower, Pittsburgh, PA 15261 (E-mail: paf10{at}pitt.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.
March 12, 2002;10.1152/ajprenal.00346.2001
Received 20 November 2001; accepted in final form 6 March 2002.
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