Department of Physiology University of Maryland School of Medicine Baltimore, Maryland 21201
THIS
ISSUE OF the American Journal of Physiology:
Renal Physiology contains two important papers describing the
immunolocalization of transporters in the distal tubules of the mouse
(3, 6). There are many reasons for the special interest in
the organization of this region of the mouse nephron. The distal
convoluted tubule (DCT) plays a critical role in regulating renal Na,
Ca, and Mg excretion and is a site where several inherited disorders
disrupt the normal inverse relationship between Na and Ca transport.
The availability of antibodies to proteins that occur in the DCT has made possible localization studies to provide a topological map of this
nephron segment.
For a number of years, this enterprise has focused on the rat and
rabbit. Studies showed that transporters are distributed uniformly
along the length of the DCT in the rabbit, but they uncovered
surprisingly great regional differences in the rat (1, 10). The group led by Bachmann and Ellison defined two
subsegments of the rat DCT: 1) DCT1, which expresses the
thiazide-sensitive NaCl cotransporter (NCC or TSC) but not the
Na+/ Ca2+ exchanger (NCX); and 2)
DCT2, which expresses both NCC and NCX. As in the rabbit, they found
that the adjacent connecting tubule (CNT) of the rat expresses NCX but
not NCC. Later work established that within the DCT only DCT2 expresses
ENaC (7, 8, 11) and the enzyme 11 Given the growing number of knockout mice available for studies of
kidney function, the present issue provides two important studies
designed to examine the distribution of transport proteins in the
mouse. In most respects, the two papers are remarkably consistent in
their findings. They show that the mouse distal tubule is really
different from that in either the rat or the rabbit (3,
6). NCX and calbindin D28K do not define a distinct region as in the rat nor is the segment like that in the rabbit. There
is a region in the late portion of the DCT where NCC overlaps with the
epithelial Na channel (ENaC) and the epithelial Ca channel (ECaC)
identified by the Bindels group (5). This makes for a
spirited debate between the papers as to the length of this region and
what the DCT subsegments should be called. Because analysis of
the rat relied on the low abundance of NCX marker to define DCT1,
Câmpean et al. (3) are reluctant to apply the DCT1
designation to a region that expresses NCX directly from its origin in
the adjacent thick ascending limb. The localizations do show variation
along the DCT. NCX is more abundant in late DCT, and 11 Careful readers will notice that the description of parvalbumin
localization also differs somewhat between the two papers. The possible
reason for or significance of this difference is not clear, but this
and the divergent assessment of the DCT2 length may reflect real
differences between the mice studied. Although there is a real
possibility that strain and diet differences affect renal physiology
and structure (see Ref. 9 for a recent review), these do
not appear to be significant variables between the two studies. It
turns out, however, that the group of Loffing et al. (6)
studied female mice whereas Câmpean et al. (3)
studied males. Although age or another variable other than sex may be more important, the observed differences suggest that DCT2 length, and
possibly parvalbumin distribution in the kidney, may vary in a
physiologically important way between different groups of mice. Thus
the differences between the two reports may well be telling us
something important. Resolution of this issue will require quantitative
data on the length of the two regions in different groups of mice.
To summarize, the two papers taken together develop three themes:
something old, something borrowed, and something new. What is old is
that the DCT varies among species. The mouse is neither like the rat
nor the rabbit. This suggests that the segment may be the "utility"
player in the nephron. The variable inventory of proteins along this
region may adjust for important variations in electrolyte homeostasis
among species.
What is borrowed in the story is that the DCT varies along its length
in a pattern more similar to that in the rat than the rabbit. In the
region beyond the macula densa, there is a short region that lacks NCC,
followed suddenly by a region with strong levels of NCC. After that,
Loffing et al. (6) identified a region that expresses ENaC
and ECaC, as well as NCC. Although this region may be variable and
generally shorter in the mouse than in the rat, its presence in the
mouse confirms the existence of cells where the NCC cotransporter
functionally coexists with ENaC and ECaC channels. Because
Câmpean et al. (3) found only very short and
occasional regions where NCC overlaps with 11 There are also important new insights that come from these studies.
First, we need to be careful using markers like NCX and calbindin
D28K to define the DCT2 region because the mouse studies show that these markers occur in other regions as well. Second, the
work makes clear that ECaC is not expressed at sites where other
proteins involved in Ca handling are expressed. This raises the
intriguing possibility that there are other channels for
Ca2+ entry or that these proteins can subserve other
functions. Loffing et al. (6) speculate that the early DCT
may function in magnesium transport. Clearly, the organization of the
distal nephron is complex, interesting, and important. And the story is
not over.
ARTICLE
TOP
ARTICLE
REFERENCES
-hydroxysteroid
dehydrogenase type 2 (11
HSD2) (2). This enzyme has been
shown to play a key role in conferring mineralocorticoid selectivity on
cells (see Ref. 4 for a recent review).
HSD2 can be
detected as overlapping with NCC only in the terminal portion of the
DCT. Because the paper by Loffing et al. (6) shows that
ENaC and ECaC begin to be expressed in the late region of the DCT, just
as in the rat, they prefer to describe that region as DCT2. Thus the
major data of the two papers fit together even though the groups don't
agree on nomenclature.
HSD2, we can wonder
whether transport by these cells in the mouse is dominated by glucocorticoids.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: J. B. Wade, Dept. of Physiology, Univ. of Maryland, 655 West Baltimore St., Baltimore, MD 21201 (E-mail:jwade{at}umaryland.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.
![]() |
REFERENCES |
---|
![]() ![]() ![]() |
---|
1.
Bachmann, S,
Velazquez H,
Obermüller N,
Reilly RF,
Moser D,
and
Ellison DH.
Expression of the thiazide-sensitive Na-Cl cotransporter by rabbit distal convoluted tubule cells.
J Clin Invest
96:
2510-2514,
1995[ISI][Medline].
2.
Bostanjoglo, M,
Reeves WB,
Reilly RF,
Velazquez H,
Robertson N,
Litwack G,
Morsing P,
Dorup J,
Bachmann S,
and
Ellison DH.
11Beta-hydroxysteroid dehydrogenase, mineralocorticoid receptor, and thiazide-sensitive Na-Cl cotransporter expression by distal tubules.
J Am Soc Nephrol
9:
1347-1358,
1998[Abstract].
3.
Câmpean, V,
Kricke J,
Ellison DH,
Luft FC,
and
Bachmann S.
Localization of thiazide-sensitive NaCl cotransport and associated gene products in mouse DCT.
Am J Physiol Renal Physiol
281:
F1028-F1035,
2001
4.
Farman, N,
and
Rafestin-Oblin ME.
Multiple aspects of mineralocorticoid selectivity.
Am J Physiol Renal Physiol
280:
F181-F192,
2001
5.
Hoenderop, JG,
van der Kemp AW,
Hartog A,
van de Graaf SF,
Van Os CH,
Willems PH,
and
Bindels RJ.
Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia.
J Biol Chem
274:
8375-8378,
1999
6.
Loffing, J,
Loffing-Cueni D,
Valderrabano V,
Klausli L,
Hebert SC,
Rossier BC,
Hoenderop JG,
Bindels RJ,
and
Kaissling B.
Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron.
Am J Physiol Renal Physiol
281:
F1021-F1027,
2001
7.
Loffing, J,
Pietri L,
Aregger F,
Bloch-Faure M,
Ziegler U,
Meneton P,
Rossier BC,
and
Kaissling B.
Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets.
Am J Physiol Renal Physiol
279:
F252-F258,
2000
8.
Loffing, J,
Zecevic M,
Feraille E,
Kaissling B,
Asher C,
Rossier BC,
Firestone GL,
Pearce D,
and
Verrey F.
Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK.
Am J Physiol Renal Physiol
280:
F675-F682,
2001
9.
Meneton, P,
Ichikawa I,
Inagami T,
and
Schnermann J.
Renal physiology of the mouse.
Am J Physiol Renal Physiol
278:
F339-F351,
2000
10.
Obermüller, N,
Bernstein P,
Velazquez H,
Reilly R,
Moser D,
Ellison DH,
and
Bachmann S.
Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney.
Am J Physiol Renal Fluid Electrolyte Physiol
269:
F900-F910,
1995
11.
Schmitt, R,
Ellison DH,
Farman N,
Rossier BC,
Reilly RF,
Reeves WB,
Oberbaumer I,
Tapp R,
and
Bachmann S.
Developmental expression of sodium entry pathways in rat nephron.
Am J Physiol Renal Physiol
276:
F367-F381,
1999