COMMENTARY
Distribution of transporters along the mouse distal nephron: something old, something borrowed, something new

J. B. Wade

Department of Physiology University of Maryland School of Medicine Baltimore, Maryland 21201


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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 11beta -hydroxysteroid dehydrogenase type 2 (11beta 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).

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 11beta 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.

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 11beta HSD2, we can wonder whether transport by these cells in the mouse is dominated by glucocorticoids.

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.


    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.


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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[Abstract/Free Full Text]. First published August 8, 2001; 10.1152/ajprenal.00148.2001.

4.   Farman, N, and Rafestin-Oblin ME. Multiple aspects of mineralocorticoid selectivity. Am J Physiol Renal Physiol 280: F181-F192, 2001[Abstract/Free Full Text].

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[Abstract/Free Full Text].

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[Abstract/Free Full Text]. First published August 15, 2001; 10.1152/ajprenal.00085.2001.

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[Abstract/Free Full Text].

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[Abstract/Free Full Text].

9.   Meneton, P, Ichikawa I, Inagami T, and Schnermann J. Renal physiology of the mouse. Am J Physiol Renal Physiol 278: F339-F351, 2000[Abstract/Free Full Text].

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[Abstract/Free Full Text].

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[Abstract/Free Full Text].


Am J Physiol Renal Fluid Electrolyte Physiol 281(6):F1019-F1020
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