INVITED REVIEW
In vivo role of CLC chloride channels in the kidney
Shinichi
Uchida
Second Department of Internal Medicine, Tokyo Medical and Dental
University, School of Medicine, Tokyo 113-8519, Japan
 |
ABSTRACT |
Chloride channels in the kidney are involved in important
physiological functions such as cell volume regulation, acidification of intracellular vesicles, and transepithelial chloride transport. Among eight mammalian CLC chloride channels expressed in the kidney, three (CLC-K1, CLC-K2, and CLC-5) were identified to be related to
kidney diseases in humans or mice. CLC-K1 mediates a transepithelial chloride transport in the thin ascending limb of Henle's loop and is
essential for urinary concentrating mechanisms. CLC-K2 is a basolateral
chloride channel in distal nephron segments and is necessary for
chloride reabsorption. CLC-5 is a chloride channel in intracellular
vesicles of proximal tubules and is involved in endocytosis. This
review will cover the recent advances in research on the CLC chloride
channels of the kidney with a special focus on the issues most
necessary to understand their physiological roles in vivo, i.e.,
their intrarenal and cellular localization and their phenotypes of
humans and mice that have their loss-of-function mutations.
knockout mice; immunohistochemistry; nephrogenic diabetes
insipidus; Bartter's syndrome; Dent's disease
 |
INTRODUCTION |
SINCE THE
INITIAL CLONING of the CLC family, the isolation of CLC-0 from
the electric organ of Torpedo marmorata by an
expression cloning strategy (15), nine mammalian CLCs have
been cloned by using homology-based cloning methods (1, 3,
14, 18, 19, 35, 42, 43, 45, 46). With the exception of CLC-1, a
chloride channel specific to the skeletal muscle, all of the other
eight CLCs are expressed in the kidney. However, the physiological roles of most of these channels have not yet been established. To
determine the in vivo role of each channel, we must first ascertain its
immunolocalization in tissues and cells, as well as its functional characteristics. However, specific antibodies to each CLC channel have
not been generated with great success. So far, reports on immunolocalization have been published on only three CLCs [CLC-K1 (47, 48), CLC-K2 (48, 49), and CLC-5
(5, 10, 25, 36)] in the kidney. The difficulty in
generating antibodies may be due to the high homology between CLC
channels, i.e., CLC-K1 and CLC-K2; CLC-3, CLC-4, and CLC-5. On the
other hand, functional expression studies have not necessarily given us
definitive clues to elucidate the physiological role of CLC channels in
vivo because some of them could not be expressed in heterologous
expression systems and the results have not been consistent among the
researchers (1, 6, 7, 16, 17, 19, 35, 43, 46). Recently, two human genetic approaches have clearly determined important physiological roles of CLC-5 and CLC-Kb in kidney (23,
39). In addition, we recently generated CLC-K1-knockout mice and
found that the Clcnk1
/
mice showed nephrogenic diabetes
insipidus (27). The impact of these studies has clarified
the physiological relevance of CLC chloride channels in the kidney and
highlighted the importance of these genetic approaches in
characterizing the physiological roles of channels and transporters in
this organ.
 |
CLC-K1 AND CLC-K2 CHLORIDE CHANNELS |
Molecular Cloning and Intrarenal Localization
CLC-K1 (46) and CLC-K2 (1) were isolated
by using a PCR-based cloning strategy from rat kidney. These chloride
channels are highly homologous proteins (~80% amino acid identity),
each consisting of 687 amino acids. Later, Kieferle et al.
(19) reported the cloning of two human CLC-K channels and
tentatively named them CLC-Ka and CLC-Kb. Because the amino acid
identity between human CLC-Ka and CLC-Kb was >90%, sequence
comparison did not tell us which clone corresponded to K1 or K2 in
rats. We also cloned a human CLC-K channel that we identified as a
human homolog of rat CLC-K2 on the basis of its localization in the
human kidney (44). This clone turned out to be identical
with CLC-Kb (19). In other species, Zimniak et al.
(51, 52) cloned a rabbit CLC-K channel and designated it
as rbClC-Ka. Again, nucleotide comparison did not tell us whether
rbClC-Ka was CLC-K1 or K2. Very recently, Maulet et al.
(28) reported the isolation of the Xenopus
laevis CLC-K channel. There are also two CLC-K channels from mice
deposited by Zimniak et al. in GenBank (accession nos. AF124847 and AF124848), and we knocked out one of them, AF124848. Although this channel is named the CLC-K channel in
the cortical thick ascending limb of Henle's loop (cTAL), our immunohistochemistry (27) clearly showed that it is a
mouse homolog of rat CLC-K1 (see Fig. 1).

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Fig. 1.
Immunohistochemistry of CLC-K channels in the mouse kidney.
Left: in CLC-K1-knockout mice, there was no staining in the
inner medulla (IM), confirming the knockout of mouse CLC-K1. This
antiserum initially raised against rat CLC-K1 recognized both K1 and K2
in mice. The basolateral staining of the thick ascending limb of
Henle's loop, i.e., mouse CLC-K2 staining, was observed in the outer
medulla (OM) of the CLC-K1-knockout mice.
Magnification: ×100. Right: mouse CLC-K1
immunostaining was observed in the inner medulla of wild-type mice
kidney by using anti-rat CLC-K1 antibody (46).
Magnification: ×100.
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Exact intrarenal localization of two CLC-K channels was clearly
determined by a recent in situ hybridization study in which CLC-K1- and
-K2-specific riboprobes were prepared in the 3'-untranslated regions.
This study verified our initial immunohistochemical study on CLC-K1
(47) and also showed that CLC-K1 and CLC-K2 are not colocalized. Immunohistochemistry revealed that CLC-K1 is restricted in
the thin ascending limb of Henle's loop (tAL) and that it is present
in both the apical and basolateral plasma membranes (47). The presence of CLC-K1 in both plasma membranes explains why tAL possesses an extraordinarily high chloride permeability
(13) and why TAL having CLC-K2 only on the
basolateral side shows much less transepithelial chloride permeability.
In contrast to the restricted localization of CLC-K1, CLC-K2 showed a
relatively broader expression pattern in distal nephrons
(50). In situ hybridization revealed that CLC-K2 is
expressed abundantly in the distal tubules, connecting tubules, and
cortical collecting ducts (50). There is also moderate
expression in the medullary TAL (mTAL). As for the cellular
localization of CLC-K2, there has been no report using a
CLC-K2-specific antibody. In the study by Vandewalle et al.
(48), an antibody recognizing both CLC-K1 and CLC-K2
stained the basolateral plasma membranes of the distal nephrons,
including inner medullary collecting ducts. Winters et al.
(49) reported that rbCLC-Ka was present in the basolateral plasma membranes of mTAL and in the cytoplasm of intercalated cells of
collecting ducts. Recently, we found in an analysis of CLC-K1-knockout
mice that our antiserum specific to rat CLC-K1 recognized both CLC-K1
and CLC-K2 in mice (K. Kobayashi and S. Uchida, unpublished
observations; see Fig. 1). Accordingly, we could observe CLC-K2
immunohistochemistry in the section of Clcnk1
/
mice. Specifically, we could observe a basolateral staining of CLC-K2
in the mTAL, distal tubules, and connecting tubules in that section.
There was no immunoreactivity in the collecting ducts in the inner
medulla. These results were highly consistent with our in situ
hybridization study in rats (50). Taken in sum, the
findings from all these studies suggest that CLC-K2 is a
basolateral chloride channel in the nephron segment where
sodium-dependent chloride transporters (furosemide-sensitive Na-K-2Cl
cotransporter and thiazide-sensitive Na-Cl cotransporter) are present
in the apical plasma membranes. This suggested a role of CLC-K2 as a route for vectorial transepithelial chloride transport (reabsorption). Figure 2 shows the localization of
various CLC channels along the nephron.

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Fig. 2.
Intrarenal and cellular localization of CLC-K1, CLC-K2,
and CLC-5. In humans, CLC-K1 and CLC-K2 were named ClC-Ka and ClC-Kb,
respectively (19). Rabbit homolog of CLC-K2 was named
rbClC-Ka (51, 52).
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Nephrogenic Diabetes Insipidus in Clcnk1
/
Mice and
Bartter's Syndrome in Patients with CLCNKB Mutations
Before we generated CLC-K1-knockout mice, Simon et al.
(39) reported mutations of the CLCNKB gene in
patients with Bartter's syndrome. As mentioned above,
localization of CLC-K2 in the kidney suggested the role of CLC-K2 in
chloride reabsorption in distal nephrons. Reduction of chloride
reabsorption in these nephron segments was known to cause hypovolemic
hypokalemic alkalosis, and Simon et al. (40, 41) actually
found mutations of genes encoding furosemide-sensitive Na-K-2Cl
cotransporter and thiazide-sensitive Na-Cl cotransporter in patients
with Bartter's and its variant, Gitelman's syndrome, respectively.
Accordingly, the CLCNKB gene (human gene of CLC-K2) became
the third gene with mutations known to cause Bartter's syndrome. This
study clearly demonstrated the anticipated role of CLC-K2 in the
kidney, i.e., as a route for chloride reabsorption to maintain
extracellular volume. More direct evidence will be obtained by a
microperfusion study of TAL from the Clcnk2
/
mice.
In contrast to CLC-K2, CLC-K1 is present only in the tAL. Considering
its structural similarity to CLC-K2 and its plasma membrane localization, there was no doubt that CLC-K1 was also involved in the
transepithelial chloride transport in tAL. However, no loss-of-function
mutation was found in the CLCNKA gene (human CLC-K1 gene) in
patients with Bartter's syndrome (39). This suggested
that chloride transport in the tAL may not be involved in the
regulation of chloride balance in the extracellular space. Rather,
CLC-K1 may well be involved in urinary concentrating mechanisms as an
important component of countercurrent systems. To directly verify
this possibility, we generated CLC-K1-knockout mice
(27). Immunohistochemistry revealed the selective
deletion of the CLC-K channel in the tAL, i.e., CLC-K1 (Fig. 1). In a
microperfusion study of the tAL of Clcnk1
/
mice, we
could clearly conclude that the transepithelial chloride
transport in the tAL is mediated by CLC-K1 (27). As
expected, knockout of chloride transport in the tAL resulted in
polyuria that was insensitive to deamino-Cys1,
D-Arg8 vasopressin (dDAVP) administration,
i.e., nephrogenic diabetes insipidus (Fig.
3). We recently confirmed that this
polyuria was the result of water diuresis, not solute diuresis (N. Akizuki and S. Uchida, unpublished observations). This indicated that, unlike the mutation of CLC-K2 in humans, the change of transpithelial chloride transport in the tAL did not affect chloride clearance. On the
other hand, direct measurement of inner medullary osmolarity was
reduced in the Clcnk1
/
mice in both hydrated and
dehydrated conditions. In addition, both NaCl and urea accumulation
were impaired in the Clcnk1
/
mice. The decrease in NaCl
accumulation could be anticipated because the tAL is a main site of
NaCl supply to the interstitium of the inner medulla. However, the
impairment of urea accumulation suggested that a mechanism(s) for
generating hypertonic inner medulla is not a sum of transport systems
independently functioning but a system consisting of various transport
systems interacting with each other, i.e., a countercurrent system(s).

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Fig. 3.
Urine osmolarity before (pre) and after intraperitoneal
injection of deamino-Cys1, D-Arg8
vasopressin (dDAVP; post). Filled bars, before injection; hatched bars,
after injection. Data are means ± SE (n = 4). In
the CLC-K1-knockout mice, the urine osmolarity (U-Osm) was not
significantly increased by intraperitoneal injection of dDAVP
(27).
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CLC-3, -4, AND -5 |
Molecular Identification and Intrarenal and Cellular
Localization
CLC-5 encodes a 746-amino acid protein and forms a subbranch with
CLC-3 (17, 18) and CLC-4 (14). Although these
three CLC channels possess only ~30% amino acid identity with other CLC branches, they share ~80% identity amongst themselves, and this
has made the generation of specific antibodies difficult. In rats,
CLC-5 is expressed abundantly in kidney, and much lower expression is
observed in the colon, brain, and liver (35, 43). CLC-3
expression has been observed in various rat tissues including the
kidney (18). Rat CLC-4 is expressed in the skeletal
muscle, heart, kidney, brain, and liver (14). Thus all
three of these channels are expressed in the kidney. Information on the
localization of these CLC channels in the kidney was scant until the
appearance of four recent papers on the intrarenal and cellular
localization of CLC-5 (5, 10, 25, 36). Still, there has
been no report on the localization of CLC-4 in the kidney, and only one
in situ hybridization study revealed that CLC-3 is expressed in the
intercalated cells (type B) of collecting ducts (32). As
for CLC-5 localization, Gunther et al. (10) first reported
rat CLC-5 immunolocalization in kidney by using polyclonal antibody
raised against a synthetic peptide as an antigen. CLC-5 was present in
the endocytotic vesicles of S1, S2, and S3 segments of the proximal
tubules in this study. It was concentrated below microvilli of the
brush border and colocalized with H+-ATPase. In
intercalated cells of collecting ducts, it again localizes to apical
intracellular vesicles and colocalizes with H+-ATPase in
-intercalated cells. Very recently, we reported mouse CLC-5
immunolocalization using a monoclonal antibody raised against a
synthetic peptide as an antigen (36). The results were
basically similar to those on rat CLC-5 reported by Günther et
al. (10). On the other hand, Luyckx et al.
(25) reported CLC-5 staining in the S3 segment of proximal
tubules and mTAL but not in the intercalated cells. They raised
antisera against a CLC-5 fusion protein and immunoabsorbed CLC-3 and
CLC-4 reactivity to generate CLC-5-specific antiserum. The discrepancy
between this study and the former two cannot be explained merely by
species difference or differences in methodology. Luyckx et al. claimed
that the CLC-5 staining reported by Gunther et al. (10)
could be staining of CLC-3 and/or CLC-4, instead of CLC-5.
Determination of specificity of polyclonal antibodies is sometimes very
difficult, especially when closely related molecules are present. The
fact that our monoclonal data corroborated the report by Gunther but
not that by Luyckx et al. (25) suggested that the staining
of the subapical vesicles in proximal tubule and intercalated cells may
not be the staining of CLC-3 and/or CLC-4, but rather of CLC-5 (Fig. 2). Another CLC-5 immunohistochemical study by Devuyst et al. (5) did not convincingly support either of these
discrepant results. They showed human CLC-5 localization in proximal
tubules, TAL, and intercalated cells of collecting ducts by using an
immunoabsorbed CLC-5-specific polyclonal antibody raised against a
synthetic peptide corresponding to CLC-5 extracellular domains
(5). The staining in the proximal tubules and intercalated
cells appeared broadly cytoplasmic and did not colocalize with
H+-ATPase. Taken together, these findings do not yet
provide a definitive answer on the localization of CLC-3, CLC-4, and
CLC-5 in the kidney. Immunostaining of kidney sections of patients or
animals deficient in each CLC channel may be the best way to determine
the specificity of antibodies.
CLCN5 Mutations in Human Kidney Diseases
Mutations in CLCN5 (the human gene of CLC-5) were found
in three disorders associated with hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked
recessive hypophophatemic rickets (22, 23, 34). Later,
several groups including our own identified CLCN5 mutations in Japanese patients with low-molecular-weight proteinuria (LMWP) (2, 12, 24, 30, 31), a disease first reported about 20 years ago in children. Because there is an annual urinary screening system for children in Japan, asymptomatic children with LMWP can often
be found. As a result, we could find the mutations of the
CLCN5 gene in patients with LMWP as a sole phenotype
(30). It is not known whether these patients will remain
asymptomatic or will develop various symptoms other than LMWP in the
future. In any case, the existence of patients having the
CLCN5 gene mutations who showed only LMWP suggested that
LMWP is a common and essential manifestation of the dysfunction of
CLC-5. It is well known that low-molecular-weight proteins are
reabsorbed in the proximal tubules by endocytotic processes.
Accordingly, the localization of CLC-5 in the endosomes of proximal
tubules and the colocalization with H+-ATPase shown by
Günther et al. (10) and our own group
(36) neatly explain the pathogenesis of this essential
phenotype of CLC-5 disorder. However, there are still several
unresolved problems in the pathogenesis of various phenotypes in
Dent's disease and X-linked recessive nephrolithiasis if the primary
defect in the CLC-5 channel disorder is assumed to be a defect of
endocytosis in the proximal tubules. For example, CLC-5 current
expressed on heterologous expression systems (43) did not
fit with the expected characteristics of chloride channels in
endosomes. Even if CLC-5 is assumed to be present in mTAL, an important
site for calcium reabsorption, it is still difficult to explain how an intracellular chloride channel can be involved in calcium transport in
mTAL. Very recently, Silva et al. (38) reported that
parathyroid hormone (PTH) modulated the expression of CLC-5
in the kidney cortex but that neither 1
,25(OH)2
vitamin D3 nor PTH regulated CLC-5 expression in the
medulla. This suggested that CLC-5 could be involved in calcium
homeostasis, but the exact mechanism is still obscure. To solve these
problems, a CLC-5-deficient animal model may be necessary. Recently,
Luyckx et al. (26) reported a mouse model of reduced CLC-5
expression investigated by a ribozyme approach. Surprisingly, the
transgenic ribozyme-expressing animals showed no obvious phenotype
except for a slight hypercalciuria. LMWP was not mentioned in their
study. Thus we have to wait for the real CLC-5-knockout mice to answer
the above unresolved problems.
The physiological roles of CLC-3 and CLC-4 in vivo remain to be
determined. Duan et al. (6) reported CLC-3 as a
volume-regulated chloride channel. Considering their structural
similarity to CLC-5, however, CLC-3 and CLC-4 may also be intracellular
chloride channels. To clarify their physiological roles, their exact
cellular localization and the use of knockout animals or cells will
first be necessary.
 |
OTHER CLC CHLORIDE CHANNELS |
There has been no mention thus far in this report of three other
mammalian CLC chloride channels, CLC-2 (32), CLC-6
(4, 20), and CLC-7 (20). Although their
functions and tissue distributions have been partially characterized,
their physiological roles in vivo still remain somewhat obscure because
of the lack of information on exact cellular localization. Yeast has
one CLC gene, GEF1, which is involved in ionic homeostasis
of intracellular organelles (8, 9). CLC-3 and CLC-5
homolog were also cloned from A6 X. laevis renal cells
(21) and gills of Oreochromis mossambicus. (29). In addition, Arabidopsis thaliana is
known to have four CLC channels, one of which (AtCLC-d) functions as an
intracellular chloride channel (11). Recently, nematode
was found to have six CLC chloride channels (37).
Petalcorin et al. (33) reported that one
(clh-1) of the null mutations caused a significantly wider
body and that this condition was restored to normal by high osmolarity
in the culture medium. The authors speculated that clh-1 is
somehow involved in the osmoregulation.
 |
FUTURE DIRECTIONS |
Recent human genetic studies (23, 39) have determined
the in vivo roles of CLC-K2 and CLC-5 in the kidney. Research on ion
channels can benefit tremendously from the discovery of channel diseases in humans. Naturally occurring mutations causing diseases show
us regions of functional importance in the channels and give us
important information on the structure-function relationship of channel
proteins. However, it is not always possible to find mutations of a
gene of interest in humans. Accordingly, a generation of knockout
animals is an important strategy in the study of the physiological role
of a gene of interest. In addition, as in the case of CLC-5, a mouse
model must be generated to understand the exact mechanisms of a disease
even after loss-of-function mutations were found in humans. There still
remain CLC channels with unknown in vivo functions, for which knockout
mice must be generated and analyzed in the future. Cellular
localization of a channel protein and its regulation (intracellular
sorting mechanisms) are also important issues in understanding channel
physiology. In research on mammalian CLC chloride channels, cellular
localization at the electron microscopy level has only been studied
with regard to CLC-K1 and CLC-5, and there has not been a report on
sorting mechanisms within cells. More studies on this issue should be
performed in the future because functions of CLC chloride channels
could be regulated at the level of intracellular trafficking of channel proteins. It is also not known whether CLC chloride channels are associated with a variety of molecules to achieve the physiological function of the ion channels. The failure to express some CLC chloride
channels in heterologous expression systems suggests this possibility.
Identification of such associated proteins could also help to clarify
the unknown physiological role of CLC channels.
 |
ACKNOWLEDGEMENTS |
This work was supported in part by the Salt Science Research
Foundation and Grants-in-Aid from the Ministry of Education, Science,
Sport, and Culture of Japan.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: S. Uchida, Second Dept. of Internal Medicine, Tokyo Medical and Dental Univ., School of Medicine, 1-5-45 Yushima Bunkyo Tokyo,
113-8519 Japan (E-mail: suchida.med2{at}med.tmd.ac.jp).
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.
 |
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