Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel

Nature Genetics volume 21, pages 95–98 (1999)Cite this article

Abstract

CLC-K1 is a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) in the inner medulla 1, 2 . Transport of NaCl in the tAL is thought to be a component of urinary concentration in a passive model of the countercurrent multiplication system 3, 4, 5 , but there has been no direct evidence that CLC-K1 is involved in urine concentration. To analyse the physiological function of CLC-K1 in vivo , we generated mice lacking CLC-K1 by targeted gene disruption. Clcnk1 –/– mice were physically normal appearance, but produced approximately five times more urine than Clcnk1 +/– and Clcnk1 +/+ mice. After 24 hours of water deprivation, Clcnk1 –/– mice were severely dehydrated and lethargic, with a decrease of approximately 27% in body weight. Intraperitoneal injection of the V2 agonist 1-deamino-8-D-arginine vasopressin (dDAVP) induced a threefold increase in urine osmolarity in Clcnk1 +/– and Clcnk1 +/+ mice, whereas only a minimal increase was seen in Clcnk1 –/– mice, indicating nephrogenic diabetes insipidus. After in vitro perfusion of the tAL, the lumen-to-bath chloride gradient did not produce a diffusion potential in Clcnk1 –/– mice in contrast to Clcnk1 +/+ and Clcnk1 +/– mice. These results establish that CLC-K1 has a role in urine concentration, and that the countercurrent system in the inner medulla is involved in the generation and maintenance of hypertonic medullary interstitium.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted disruption of Clcnk1.
Figure 2: Immunohistochemistry of Clcnk1+/+ and Clcnk1–/– mouse kidney.
Figure 3: Urine concentration ability of Clcnk1+/+, Clcnk1+/– and Clcnk1–/– mice.
Figure 4: In vitro microperfusion study of the thin limb of Henle's loop.

Similar content being viewed by others

References

  1. Uchida, S. et al. Molecular cloning of a chloride channel that is regulated by dehydration and predominantly expressed in kidney medulla. J. Biol. Chem. 268, 3821–3824 ( 1993).

    CAS  PubMed  Google Scholar 

  2. Uchida, S. et al. Localization and functional characterization of rat kidney-specific chloride channel, ClC-K1. J. Clin. Invest. 95, 104–113 (1995).

    Article  CAS  Google Scholar 

  3. Imai, M. & Kokko, J.P. Mechanism of sodium and chloride transport in the thin ascending limb of Henle. J. Clin. Invest. 58, 1054–1060 ( 1976).

    Article  CAS  Google Scholar 

  4. Kokko, J.P. & Rector, F.C. Jr Countercurrent multiplication system without active transport in inner medulla. Kidney Int. 2, 214–223 ( 1972).

    Article  CAS  Google Scholar 

  5. Imai, M., Taniguchi, J. & Tabei, K. Function of thin loop of Henle. Kidney Int. 31, 565–579 ( 1987).

    Article  CAS  Google Scholar 

  6. Simon, D.B. et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet. 17, 171–178 (1997).

    Article  CAS  Google Scholar 

  7. Kieferle, S., Fong, P., Bens, M., Vandewalle, A. & Jentsch, T.J. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc. Natl Acad. Sci. USA 91, 6943–6947 ( 1994).

    Article  CAS  Google Scholar 

  8. Takeuchi, Y., Uchida, S., Marumo, F. & Sasaki, S. Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney. Kidney Int. 48,1497– 1503 (1995).

    Article  CAS  Google Scholar 

  9. Kondo, Y., Yoshitomi, K. & Imai, M. Effect of anion transport inhibitors and ion substitution on Cl transport in the thin ascending limb of Henle's loop. Am. J. Physiol. 253, F1206–F1215 (1987).

    CAS  PubMed  Google Scholar 

  10. Kondo, Y., Yoshitomi, K. & Imai, M. Effect of pH on Cl- transport in the thin limb ascending limb of Henle's loop. Am. J. Physiol. 253, F1216–F1222 (1987).

    CAS  PubMed  Google Scholar 

  11. Yoshitomi, K., Kondo, Y. & Imai, M. Evidence for conductive Cl pathways across the cell membranes of the thin ascending limb of Henle's loop. J. Clin. Invest. 82 , 866–871 (1988).

    Article  CAS  Google Scholar 

  12. Lolait, S.J. et al. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature 357, 336–339 (1992).

    Article  CAS  Google Scholar 

  13. Rosenthal, W. et al. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 359, 233–235 (1992).

    Article  CAS  Google Scholar 

  14. Deen, P.M.T. et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264, 92–95 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Nakayama and K.-i. Nakayama for helpful advice. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Authors and Affiliations

  1. Second Department of Internal Medicine, Tokyo Medical and Dental University, School of Medicine, Japan

    Yoshihiro Matsumura, Shinichi Uchida, Hiroaki Miyazaki, Shigeru B.H. Ko, Atsushi Hayama, Sei Sasaki & Fumiaki Marumo

  2. Department of Pediatrics, Tohoku University, School of Medicine, Japan

    Yoshiaki Kondo, Tetuji Morimoto & Wen Liu

  3. Nippon Roche Research Center, Japan

    Mikio Arisawa

Authors
  1. Yoshihiro Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinichi Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiaki Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigeru B.H. Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atsushi Hayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tetuji Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mikio Arisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sei Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fumiaki Marumo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinichi Uchida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsumura, Y., Uchida, S., Kondo, Y. et al. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nat Genet 21, 95–98 (1999). https://doi.org/10.1038/5036

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/5036

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing