1 Institute of Anatomy, University of Zurich, CH-8057 Zurich; 2 Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520; 3 Institut de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland; and 4 Department of Cell Physiology, University Medical Centre, 6500-HB Nijmegen, The Netherlands
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ABSTRACT |
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First published August
15, 2001; 10.1152/ajprenal. 00085.2001.The organization of
Na+ and Ca2+ transport pathways along the mouse
distal nephron is incompletely known. We revealed by
immunohistochemistry a set of Ca2+ and Na+
transport proteins along the mouse distal convolution. The
thiazide-sensitive Na+-Cl
cotransporter (NCC)
characterized the distal convoluted tubule (DCT). The
amiloride-sensitive epithelial Na+ channel (ENaC)
colocalized with NCC in late DCT (DCT2) and extended to the downstream
connecting tubule (CNT) and collecting duct (CD). In early DCT (DCT1),
the basolateral Ca2+-extruding proteins
[Na+/Ca2+ exchanger (NCX), plasma membrane
Ca2+-ATPase (PCMA)] and the cytoplasmic
Ca2+-binding protein calbindin D28K (CB) were
found at very low levels, whereas the cytoplasmic
Ca2+/Mg2+-binding protein parvalbumin was
highly abundant. NCX, PMCA, and CB prevailed in DCT2 and CNT, where we
located the apical epithelial Ca2+ channel (ECaC1). Its
subcellular localization changed from apical in DCT2 to exclusively
cytoplasmic at the end of CNT. NCX and PMCA decreased in parallel with
the fading of ECaC1 in the apical membrane. All three of them were
undetectable in CD. These findings disclose DCT2 and CNT as major sites
for transcellular Ca2+ transport in the mouse distal
nephron. Cellular colocalization of Ca2+ and
Na+ transport pathways suggests their mutual interactions
in transport regulation.
mouse kidney morphology; amiloride-sensitive epithelial sodium channel; thiazide-sensitive sodium-chloride cotransporter; epithelial calcium channel; calcium-binding proteins
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INTRODUCTION |
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THE FINE-TUNING OF RENAL Na+ and Ca2+ excretion takes place in the distal nephron. It comprises several morphologically and functionally distinct subsegments, in which the apical permeability for Na+ and Ca2+ is under the control of various hormones (e.g., aldosterone, parathyroid hormone, vitamin D3) and dietary salt intake (36). Furthermore, the distal segments are targets for specific diuretic drugs that interfere with renal Na+ and Ca2+ metabolism (36).
Transcellular Na+ transport in the thick ascending
limb (TAL) is mediated by the bumetanide-sensitive
Na+-K+-2Cl cotransporter (NKCC2)
(22). In the subsequent segments, the distal convoluted
tubule (DCT) and the connecting tubule (CNT), both situated in the
cortical labyrinth, and the cortical collecting duct (CCD), situated in
the medullary rays, the apical Na+ transport pathways are
the thiazide-sensitive Na+-Cl
cotransporter
(NCC) (35) and the amiloride-sensitive epithelial Na+ channel (ENaC) (10).
Ca2+ transport in the thick ascending limb (TAL) occurs via the paracellular pathway and follows, passively, the transport of Na+. Conversely, Ca2+ transport in DCT and CNT proceeds via transcellular routes and depends on the activity of Ca2+-transporting proteins within the apical and basolateral plasma membranes of the epithelial cells (11, 17, 36). In these cells, apical Ca2+ entry is thought to be mediated by the recently identified and characterized renal epithelial Ca2+ channel (ECaC1) (16). Ca2+ is extruded at the basolateral side by a plasma membrane Ca2+-ATPase (PMCA) and a Na+/Ca2+ exchanger (NCX). Cytoplasmic Ca2+-binding proteins, such as calbindin D28K (CB) and parvalbumin (PV), might uphold the gradient for Ca2+ entry by keeping the intracellular concentration of free Ca2+ constant (17).
The above-mentioned proteins have been localized to the distal nephron of rabbit (1, 9, 15, 16, 26, 29, 37) and rat (4, 5, 10, 22, 33-35, 39, 41) but only in part in mice [e.g., NKCC2 (32), NCC (23), ENaC (6, 27), and CB (38)]. Previous studies revealed significant differences in the distribution patterns of salt and water transport proteins along the distal nephron between rabbits (1, 26) and rats (24, 33, 41). Differences among species in the arrangement of transport proteins within the distal nephron might importantly modify the overall renal electrolyte excretion pattern and limit extrapolations of functional data from one species to the other. Genetically modified mice are increasingly used to clarify the (patho)physiological roles of specific genes in renal function and electrolyte metabolism (20, 31). Some of these mouse strains are thought to represent models of genetically caused human disorders of renal electrolyte metabolism (20); yet, so far, the organization of the mouse with respect to the arrangement of transport proteins is incompletely known.
The purpose of the present study was to disclose by immunohistochemistry the organization of the mouse cortical distal nephron with respect to the precise localizations of Na+ and Ca2+ transport pathways and to determine sites of putative mutual interactions between Na+- and Ca2+-transporting proteins. We examined the distribution patterns of the Na+ transport systems NCC and ENaC in relation to proteins thought to be involved in renal Ca2+ transport, such as ECaC1, NCX, PMCA, CB, and PV. These data may constitute a basis for the interpretation of functional data on renal Na+ and Ca2+ metabolism in the mouse.
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MATERIALS AND METHODS |
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Animals. The kidneys from six adult female NMRI mice (RCC, Füllinsdorf, Switzerland) and six adult female C57BL/6 mice (Iffa Credo, Arbresle, France) were studied. The mice (body wt 24-28 g) were housed in groups of six animals and had free access to standard lab chow and tap water.
Fixation and tissue processing.
Mice were anesthetized with a combination of ketamine (Narketan 10, Chassot, Belp, Switzerland; 80 mg/kg body wt ip) and xylazine (Rompun,
Bayer, Leverkusen, Germany; 33 mg/kg body wt ip). The abdominal cavity
of each mouse was opened by a midline incision, and the abdominal aorta
was clamped downstream of the renal arteries. PE-50 tubing
(Becton-Dickinson) was inserted at the level of the iliac bifurcation
into the aorta, pushed up to the aortic clamp, and fixed by a ligature.
Then, the vena cava was opened, the aortic clamp was removed, and a
fixative solution (50 ml) was allowed to flush the mouse vasculature
under high pressure (~1.4 hp). The fixative consisted of 3%
paraformaldehyde and 0.05% picric acid. It was dissolved in a 3:2
mixture of 0.1 M cacodylate buffer (pH 7.4, adjusted to 300 mosmol/kgH2O with sucrose) and 10% hydroxyethyl starch in
saline (HAES-steril, Fresenius, Stans, Switzerland). After 5-min
fixation, the kidneys were rinsed at hydrostatic pressure by perfusion
for 5 min with the cacodylate buffer. Thereafter, the kidneys were
removed and cut into 1- to 2-mm-thick coronal slices. For
immunohistochemistry, tissue slices were frozen in liquid propane and
stored at 80°C until use.
Immunohistochemistry.
Serial sections (3-5 µm thick) were cut in a cryostat, placed on
chrome-alum gelatin-coated glass slides, thawed, and stored in PBS
until further processing. After pretreatment for 10 min with 10%
normal goat serum in PBS, the sections were incubated overnight in a
humidified chamber at 4°C with the primary antibodies (Table
1), diluted in PBS-1% BSA. Binding sites
of the primary antibodies were revealed with Cy3-conjugated donkey
anti-rabbit or anti-guinea pig IgG and with a FITC-conjugated goat
anti-mouse IgG (all secondary antibodies from Jackson Immuno Research
Laboratories, West Grove, PA).
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Segment definitions. Our description on the distribution of transport pathways along the mouse distal nephron was made according to the segment definitions used in former studies in other species (rat, rabbit). Thus the presence of NCC characterized the DCT, and the cessation of NCC defined the beginning of the CNT. For the mouse nephron, we used the subdivision of the DCT into DCT1 (NCC positive) and DCT2 (NCC and ENaC positive), originally introduced by Obermüller et al. (33) and Schmitt et al. (41) in the rat. We defined the CCD by its location in the medullary ray.
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RESULTS |
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Na+ transport pathways.
NCC immunostaining abruptly began at the sharp transition from TAL to
DCT (Fig.
1a). NCC was found in the
apical plasma membrane and in subapical vesicular structures of DCT
cells. The NCC-related immunofluorescence slightly decreased along the
last portion of the NCC-positive segment as reported previously
(27). ENaC became detectable in the late part of the DCT.
The portion in which NCC overlaps with ENaC corresponds to the DCT2.
The -ENaC subunit was not detectable with the available antibody,
unless plasma aldosterone levels of the animals were elevated by
dietary Na+ restriction (27). The
-ENaC
subunit was distinctly apparent in the apical position in the DCT2
(Fig. 1d) and became well detectable within the cytoplasm
along in the CNT and CCD (Fig. 1d). Along the early CNT, the
location of the
-ENaC subunit gradually shifted from the apical
membrane to the cytoplasm. In the more downstream CNT portions and in
the CCD, the
-ENaC subunit was found distributed in a fine granular
pattern throughout the cytoplasm exclusively (Fig. 1d).
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Ca2+-binding and -transporting proteins. Bright cytoplasmic immunostaining for PV started simultaneously with apical NCC immunostaining (Fig. 1, a and b) exactly at the transition from the TAL to the DCT and ended abruptly within the DCT (Fig. 1, a and b). In a few animals, very weak PV staining was occasionally seen in the cortical TAL and/or in DCT2.
Immunostaining for CB (the mono- and polyclonal anti-CB antibodies yielded the same staining pattern) was seen in the cytoplasm and cell nuclei of the entire DCT, CNT, and CCD, although in very different staining intensities. At the beginning of the DCT1, CB immunostaining was barely detectable, it slightly increased in a downstream direction, and steeply increased to very bright immunostaining exactly at the site where PV staining abruptly stopped (Fig. 1, b and c). The abrupt change from high PV to very high CB immunoreactivity coincided with the transition from DCT1 to DCT2. The DCT2 revealed the highest CB abundance (Fig. 1, c, e, and h). The CB staining in CNT and CCD was again weaker than in DCT2 (Fig. 1e). Intercalated cells were consistently CB negative. Immunostaining for ECaC1 started exactly at the transition from DCT1 to DCT2 (Figs. 1c and 2a) and abruptly ceased a few cells before the opening of the tubule into a CCD in the medullary ray (Fig. 2c). Thus ECaC1 immunostaining was restricted to DCT2 and CNT. The immunostaining for ECaC1 shifted in a downstream direction from a very prominent apical location in DCT2 to a progressively weaker apical and, finally, to an exclusively cytoplasmic, location. The cytoplasmic abundance also slightly decreased in a downstream direction (Figs. 1f and 2a). Intercalated cells, recognized by their prominent binding of antibodies against the vacuolar H+-ATPase (14), did not bind anti-ECaC1 antibodies (not shown).
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DISCUSSION |
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Our present study provides a comprehensive analysis of the localization and immunohistochemical abundance along the mouse distal nephron of Na+- and Ca2+-transporting proteins. Within this analysis, we describe for the first time the localization of ECaC1 in the mouse nephron. By colocalization within the same cells of the apical Ca2+ entry pathway ECaC1, basolateral Ca2+ exit pathway NCX, PMCA, and CB, the cytoplasmic Ca2+-binding protein, we define the sites along the mouse nephron with the capacity for active Ca2+ transport. The data on the organization of active Na+ and Ca2+ transport pathways along the mouse distal nephron allow one to infer on sites of complex interplay between regulatory mechanisms in distal Na+ and Ca2+ reabsorption. Our data are important for the interpretation of functional data derived from mouse strains with mutated expressions of renal transport proteins.
Our present findings on the distribution of the Na+ transport proteins in the mouse distal convolution confirm the abrupt transition from TAL to DCT and the more gradual transition from the DCT to the CNT. This organization is similar to that in rats but differs markedly from that in rabbits. Rats (41) and mice (27) display a DCT subsegment, termed DCT2 (33, 41), in which NCC overlaps with ENaC. Rabbits lack such a subsegment, and NCC and ENaC border on each other at the abrupt transition from DCT to CNT (26). Previous studies also demonstrated significant species differences with respect to the distribution of the vasopressin-dependent water channel aquaporin-2 (AQP2). In rabbit (26) the CNT is AQP2 negative, whereas in rat (24, 26) and mice (23) AQP2 is present all along the CNT.
The precise sites for transcellular Ca2+ reabsorption along the rodent distal nephron are still being debated. Micropuncture investigations of Ca2+ transport in the rat distal convolution (comprising DCT1, DCT2, CNT, and the initial CCD) tried to distinguish between the "early" (including DCT1, 2) and "late" (including CNT and initial CCD, possibly also more or less of DCT2) parts. Microperfusion studies by Costanzo (7) found similar Ca2+ transport rates in early and late distal tubules, whereas microinfusion experiments by Greger and co-workers (12) indicated that transcellular Ca2+ transport occurs predominately in the late distal tubule. Comparable measurements for the mouse do not exist. In our present study on the mouse distal nephron, we found coexpression of ECaC1, PMCA, NCX, and of CB in the DCT2 and in the CNT, with the highest immunochemical abundance in the DCT2, and a gradual decrease along the CNT. The parallel axial reduction of apical ECaC1 and of basolateral Ca2+ extrusion machinery, i.e., PMCA and NCX, indicates a progressive diminution of transcellular Ca2+ transport rates along the CNT. ECaC1, PMCA, and NCX abruptly disappeared at the transition to the CCD, consistent with the notion that transcellular Ca2+ transport is negligible in the CCD (11, 17, 36). Taken together, our findings strongly suggest that, in the mouse, the major sites of transcellular Ca2+ transport are the DCT2 and, probably to a lesser extent, the CNT. Whether Ca2+ transport occurs in DCT1 of mice, at lower rates, is unknown. The occurrence of weak but distinct immunostaining for NCX and PMCA proposes this possibility; however, in contrast to these basolateral Ca2+-transporting proteins, ECaC1, the apical entry pathway, was not detectable in DCT1. This raises the question of whether other apical Ca2+ entry pathways might play a role in transcellular Ca2+ transport in DCT1. The existence of such pathways in the DCT has been suggested by RT-PCR data obtained from isolated rat tubules (44) and an immortalized mouse DCT cell line (2).
In contrast to our findings in mouse DCT1, NCX has been reported to be absent from the DCT1 in rats (33, 41). This might point to some differences in renal Ca2+ handling between rats and mice. With respect to the localization of Ca2+-transporting proteins in DCT2 and CNT, our data from mice resemble those reported previously for rats (5, 18, 25, 33, 35, 41). In rabbits, which lack a subdivision of the DCT (1, 21, 26), all major and presently known Ca2+- transporting proteins are gathered in the CNT, indicating the CNT in this species as the major site of transcellular Ca2+ reabsorption (1, 15, 37).
The gradual changes in ECaC1 subcellular distribution along mouse distal nephron observed in our study are noteworthy. ECaC1 showed a prominent apical localization in the initial ECaC1-positive tubular portion, which gradually shifted to an exclusively intracellular localization along the CNT toward the CCD (Figs. 1f, 2a, and 3). This pattern is reminiscent of that described for the subcellular localization of ENaC (26, 27). Apical recruitment of intracellulary localized Na+ channels has been reported to occur in the CNT and CCD in response to dietary Na+ restriction (27, 30) or exogenous application of aldosterone (28). It remains to be elucidated whether the intracellularly localized ECaC1 might represent an intracellular pool of Ca2+ channels that can be recruited in response to an appropriate stimulus to the apical plasma membrane.
Clinical and experimental data have suggested profound interactions
between Na+ and Ca2+ transport within the
distal convolution (11, 36). Inhibition of NaCl
reabsorption in the DCT by thiazides, binding specifically to NCC in
the DCT, leads to hypocalciuria (11, 36). Hypocalciuria is
also a leading symptom in humans suffering from Gitelman syndrome, a
genetic disease caused by loss-of-function mutations in the NCC gene
(11, 36, 40). Similarly, mice with knockout of the NCC
gene present with hypocalciuria (42). It is thought that
the impairment of NaCl entry into the DCT cells decreases intracellular
Cl concentration and leads to hyperpolarization of the
cell and subsequent activation of apical voltage-gated Ca2+
channels (11, 17, 36). ECaC1 is activated by
hyperpolarization of the cell membrane (19). The
colocalization of both NCC and ECaC1 in the apical membrane of the
DCT2, as well as the high abundance of NCX and PMCA, in this segment
suggests that, under inhibited NaCl reabsorption via the NCC, increased
Ca2+ reabsorption might occur in the DCT2.
Also, amiloride-induced inhibition of Na+ reabsorption via ENaC provokes hyperpolarization of the apical membrane (11). The colocalization of ENaC with ECaC1 in the DCT2 and CNT could explain the increased Ca2+ reabsorption under amiloride treatment (7).
In rat kidneys, PV has been described in the distal tubule (3) along the cortical TAL, DCT, CNT, and CCD (4). In the mouse, the strict limitation of high PV abundance to the DCT1 is striking. Only occasionally, single, weakly stained PV-positive cells are found in TAL or other distal tubular portions. As discussed above, the equipping of the cell membranes in DCT1 with small numbers of Ca2+-transporting proteins makes it unlikely that the mouse DCT1 plays an important role in transcellular Ca2+ reabsorption. Thus it seems improbable that the high abundance of PV in this segment is correlated with high Ca2+ entry rates into DCT1 cells. Interestingly, although other cytoplasmic Ca2+-binding proteins, including CB, rather specifically bind Ca2+, PV has also a high affinity for magnesium (13). The DCT is the primary site for transcellular magnesium reabsorption (8). Thus it is tempting to speculate that PV might play a role in transcellular magnesium transport. The recently developed PV-knockout mouse (43) might give some clues as to the functional significance of PV in DCT1.
In conclusion, the structural and molecular organization of the distal nephron in the mouse differ markedly from that in rabbits and also, in part, from that in rats. The evidence in mice for colocalization of NCC, ENaC, and ECaC1 in DCT2 cells, as well as ENaC and ECaC1 in CNT cells, provides a morphological basis for understanding and studying the complex interplay of Na+ and Ca2+ transport in the distal nephron of this species.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Beat Schwaller (Fribourg, Switzerland) for the polyclonal parvalbumin antibody and for the suggestion to study the distribution of parvalbumin in mouse kidney.
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FOOTNOTES |
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These studies were supported by Swiss National Science Foundation Grants 31-47742.96 (to B. Kaissling) and 32-061742.00 (to J. Loffing and B. Kaissling). J. G. J. Hoenderop was supported by a grant from the European Molecular Biology Organization (ALTL 160-2000).
Part of this work was presented at the 1998 meeting of the American Society of Nephrology in Philadelphia, PA.
Address for reprint requests and other correspondence: J. Loffing or B. Kaissling, Univ. of Zurich, Institute of Anatomy, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland (E-mail: jloffing{at}anatom.unizh.ch or bkaissl{at}anatom.unizh.ch).
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.
First published August 15, 2001;10.1152/ajprenal.00085.2001
Received 13 March 2001; accepted in final form 12 June 2001.
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