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.

  • Review Article
  • Published:

Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance

Nature Clinical Practice Nephrology volume 4, pages 38–46 (2008)Cite this article

Abstract

Rodent ClC-K1 and ClC-K2, and their respective human orthologs ClCKA and ClCKB, are chloride channels specific to the kidney (and inner ear); Barttin is their functionally important subunit. ClC-K1 is predominantly localized to the thin ascending limb of the loop of Henle. ClC-K2 is expressed more broadly in the distal nephron; expression levels are highest along the thick ascending limb of the loop of Henle and distal convoluted tubule. Expression of ClC-K1 is upregulated by dehydration and downregulated by the diuretic furosemide, whereas expression of ClC-K2 is upregulated by furosemide and downregulated by high salt levels. ClCKA is important for maintenance of the corticomedullary osmotic gradient and the kidney's capacity to concentrate urine. If its ortholog, ClC-K1, is nonfunctional in mice, renal diabetes insipidus develops. ClCKB is a key determinant of tubular reabsorption of chloride and electrolytes along the distal tubule. A severe salt-losing tubulopathy (Bartter syndrome type III) develops if ClCKB is nonfunctional, whereas a common genetic variant of the CLCNKB gene that leads to increased activity of ClCKB results in salt-dependent hypertension. Disruption of the gene encoding Barttin, BSND, results in a 'double knockout' of the functions of both ClCKA and ClCKB, manifesting as Bartter syndrome type IV with sensorineural deafness and an especially severe salt-losing phenotype.

Key Points

  • ClCKA (ClC-K1) and ClCKB (ClC-K2) are chloride channels specific to the kidney (and inner ear); Barttin is their functionally important subunit

  • ClC-K1 is localized predominantly to the thin ascending limb of the loop of Henle; ClC-K2 is more broadly expressed along the distal nephron

  • ClC-K1 is upregulated by dehydration and downregulated by furosemide; the channel's human ortholog, ClCKA, is activated by the cell-volume-regulated gene SGK1; ClC-K2 is upregulated by furosemide and downregulated by high salt levels

  • ClCKA is important for maintenance of the corticomedullary osmotic gradient and for the kidney's capacity to concentrate urine; renal diabetes insipidus develops in mice if ClC-K1 is nonfunctional

  • ClCKB is important for tubular chloride and electrolyte reabsorption; a severe salt-losing tubulopathy (Bartter syndrome type III) develops if ClCKB is nonfunctional, whereas a common genetic variant of the CLCNKB gene increases the activity of ClCKB, resulting in salt-dependent hypertension

  • Dysfunction of the Barttin gene functionally corresponds to a 'double knockout' of ClCKA and ClCKB, leading to Bartter syndrome type IV with sensorineural deafness and a severe salt-losing phenotype

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: Nephron-specific localization of ClC-K2, and regulation by furosemide and a high-salt diet in rats.
Figure 2: ClC-K1 (ClCKA) is crucial for reabsorption of NaCl in the thin ascending limb of the loop of Henle.
Figure 3: ClC-K2 (ClCKB) is important for NaCl reabsorption in the thick ascending limb of the loop of Henle (and the distal convoluted tubule).
Figure 4: A model of K+ secretion in the stria vascularis of the inner ear.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Matsumara M et al. (1999) Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nature Genet 21: 95–98

    Article  Google Scholar 

  3. Birkenhäger R et al. (2001) Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29: 310–314

    Article  PubMed  Google Scholar 

  4. Schlingmann KP et al. (2004) Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350: 1314–1319

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Adachi S et al. (1994) Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts of rat kidney. J Biol Chem 269: 17677–17683

    CAS  PubMed  Google Scholar 

  7. Kieferle S et al. (1994) Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc Natl Acad Sci USA 91: 6943–6947

    Article  CAS  PubMed  Google Scholar 

  8. Waldegger S and Jentsch TJ (2000) Functional and structural analysis of ClC-K chloride channels involved in renal disease. J Biol Chem 275: 24527–24533

    Article  CAS  PubMed  Google Scholar 

  9. Estevez R et al. (2001) Barttin is a Cl− channel beta-subunit crucial for renal Cl− reabsorption and inner ear K+ secretion. Nature 414: 558–561

    Article  CAS  PubMed  Google Scholar 

  10. Waldegger S et al. (2002) Barttin increases surface expression and changes current properties of ClC-K channels. Pflügers Arch 444: 411–418

    Article  CAS  PubMed  Google Scholar 

  11. Scholl U et al. (2006) Barttin modulates trafficking and function of ClC-K channels. Proc Natl Acad Sci USA 103: 11411–11416

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lourdel S et al. (2003) A chloride channel at the basolateral membrane of the distal convoluted tubule: a candidate CLC-K channel. J Gen Physiol 121: 287–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nissant A et al. (2004) Heterogenous distribution of chloride channels along the distal convoluted tubule probed by single cell RT-PCR and patch clamp. Am J Physiol Renal Physiol 287: F1233–F1243

    Article  CAS  PubMed  Google Scholar 

  15. Nissant A et al. (2006) Similar chloride channels in the connecting tubule and cortical collecting duct of the mouse kidney. Am J Physiol Renal Physiol 290: F1421–F1429

    Article  CAS  PubMed  Google Scholar 

  16. Liantonio A et al. (2004) Investigations of pharmacologic properties of the renal CLC-K1 chloride channel co-expressed with barttin by the use of 2-(p-chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride channels blockers. J Am Soc Nephrol 15: 13–20

    Article  CAS  PubMed  Google Scholar 

  17. Picollo A et al. (2004) Molecular determinants of differential pore blocking of kidney CLC-K chloride channels. EMBO Rep 5: 584–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kobayashi K et al. (2001) Intrarenal and cellular localization of CLC-K2 protein in the mouse kidney. J Am Soc Nephrol 12: 1327–1334

    CAS  PubMed  Google Scholar 

  19. Mejia R and Wade JB (2002) Immunomorphometric study of rat renal inner medulla. Am J Physiol Renal Physiol 282: F553–F557

    Article  CAS  PubMed  Google Scholar 

  20. Takeuchi Y et al. (1995) Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney. Kidney Int 48: 1497–1503

    Article  CAS  PubMed  Google Scholar 

  21. Uchida S et al. (1998) Isolation and characterization of kidney-specific ClC-K1 chloride channel gene promoter. Am J Physiol Renal Physiol 274: F602–F610

    Article  CAS  Google Scholar 

  22. Vandewalle A et al. (1997) Localization and induction by dehydration of CLC-K chloride channels in the rat kidney. Am J Physiol 272: F678–F688

    CAS  PubMed  Google Scholar 

  23. Vitzthum H et al. (2002) Nephron specific regulation of chloride channel CLC-K2 mRNA in the rat. Kidney Int 61: 547–554

    Article  CAS  PubMed  Google Scholar 

  24. Wolf K et al. (2001) Differential gene regulation of renal salt entry pathways by salt load in the distal nephron of the rat. Pflügers Arch 442: 498–504

    Article  CAS  PubMed  Google Scholar 

  25. Wolf K et al. (2003) Parallel down-regulation of chloride channel CLC-K1 and barttin mRNA by furosemide in the thin ascending limb of the rat nephron by furosemide. Pflügers Arch 446: 665–671

    Article  CAS  PubMed  Google Scholar 

  26. Yoshikawa M et al. (1999) Localization of rat CLC-K2 chloride channel mRNA in the kidney. Am J Physiol 276: F552–F558

    CAS  PubMed  Google Scholar 

  27. Ando M and Takeuchi S (2000) mRNA encoding CLC-K1, a kidney Cl− channel is expressed in marginal cells of the stria vascularis of rat cochlea: its possible contribution to Cl− currents. Neurosci Lett 284: 171–174

    Article  CAS  PubMed  Google Scholar 

  28. Klein JD et al. (2002) Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins. Am J Physiol Renal Physiol 283: F517–F524

    Article  CAS  PubMed  Google Scholar 

  29. Embark HM et al. (2004) Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases. Kidney Int 66: 1918–1925

    Article  CAS  PubMed  Google Scholar 

  30. Debonneville C et al. (2001) Phosphorylation of Nedd4-2 by SGK1 regulates epithelial Na+ channel cell surface expression. EMBO J 20: 7052–7059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Synder PM et al. (2002) Serum and glucocorticoid-regulated kinase modulates Nedd4-2 mediated inhibition of epithelial Na+ channel. J Biol Chem 277: 5–8

    Article  Google Scholar 

  32. Jentsch TJ et al. (2005) Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest 115: 2039–2046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Waldegger S et al. (1997) Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc Natl Acad Sci USA 94: 4440–4445

    Article  CAS  PubMed  Google Scholar 

  34. Carrithers SL et al. (2004) Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Kidney Int 65: 40–53

    Article  CAS  PubMed  Google Scholar 

  35. Miyazaki H et al. (2002) Kidney-specific chloride channel, OmClC-K, predominantly expressed in the diluting segment of freshwater-adapted tilapia kidney. Proc Natl Acad Sci USA 99: 15782–15787

    Article  CAS  PubMed  Google Scholar 

  36. Uchida S et al. (2000) Transcriptional regulation of the CLC-K1 promoter by myc-associated zinc finger protein and kidney-enriched Krüppel-like factor, a novel zinc finger repressor. Mol Cell Biol 20: 7319–7331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Uchida S et al. (2001) Isolation of a novel zinc finger repressor that regulates the kidney-specific CLC-K1 promoter. Kidney Int 60: 416–421

    Article  CAS  PubMed  Google Scholar 

  38. Rai T et al. (1999) Isolation and characterization of kidney-specific CLC-K2 chloride channel gene promoter. Biochem Biophys Res Commun 261: 432–438

    Article  CAS  PubMed  Google Scholar 

  39. Kobayashi K et al. (2002) Human CLC-KB gene promoter drives the EGFP expression in the specific distal nephron segments and inner ear. J Am Soc Nephrol 13: 1992–1998

    Article  CAS  PubMed  Google Scholar 

  40. Akizuki M et al. (2001) Impaired solute accumulation in inner medulla of Clcnk1−/− mice kidney. Am J Physiol Renal Physiol 280: F79–F87

    Article  CAS  PubMed  Google Scholar 

  41. Liu W et al. (2002) Analysis of NaCl transport in thin ascending limb of Henle's loop in CLC-K1 null mice. Am J Physiol Renal Physiol 282: F451–F457

    Article  CAS  PubMed  Google Scholar 

  42. Barlassina C et al. (2007) Common genetic variants and haplotypes in renal CLCNKA genes are associated to salt-sensitive hypertension. Hum Mol Genet 16: 1630–1638

    Article  CAS  PubMed  Google Scholar 

  43. Jeck N et al. (2000) Mutations in the chloride channel gene CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res 48: 754–758

    Article  CAS  PubMed  Google Scholar 

  44. Bettinelli A et al. (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman's syndromes. J Pediatr 120: 38–43

    Article  CAS  PubMed  Google Scholar 

  45. Gitelman HJ et al. (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79: 221–235

    CAS  PubMed  Google Scholar 

  46. Jeck N et al. (2004) A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Kidney Int 65: 190–197

    Article  CAS  PubMed  Google Scholar 

  47. Jeck N et al. (2004) Activating mutation of the renal epithelial chloride channel CLC-Kb predisposing to hypertension. Hypertension 43: 1175–1181

    Article  CAS  PubMed  Google Scholar 

  48. Castrop H et al. (2000) Overexpression of chloride channel CLC-K2 mRNA in the renal medulla of Dahl salt-sensitive rats. J Hypertens 18: 1289–1295

    Article  CAS  PubMed  Google Scholar 

  49. Landau D et al. (1995) Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder. Am J Med Genet 59: 454–459

    Article  CAS  PubMed  Google Scholar 

  50. Hayama A et al. (2003) Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 119: 485–493

    Article  CAS  PubMed  Google Scholar 

  51. Jeck N et al. (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108: 1–9

    Article  Google Scholar 

  52. Shalev H et al. (2003) The neonatal variant of Bartter syndrome and deafness: preservation of renal function. Pediatrics 112: 628–633

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

BK Krämer and T Bergler contributed equally to this Review. This work was supported, in part, by the Sonderforschungsbereich 699 'Physiological, molecular, and structural determinants of renal function', TP A5 of the Deutsche Forschungsgemeinschaft DFG to BK Krämer.

Author information

Authors and Affiliations

  1. BK Krämer is Professor of Medicine and Director of Nephrology/Renal Transplantation, T Bergler is a Research Fellow and B Stoelcker is a Senior Scientist in the Klinik und Poliklinik für Innere Medizin II—Nephrologie at the University of Regensburg, Regensburg, Germany.,

    Bernhard K Krämer, Tobias Bergler & Benjamin Stoelcker

  2. S Waldegger is Professor of Pediatrics/Pediatric Nephrology in the Kinderklinik at the University of Marburg, Marburg, Germany.,

    Siegfried Waldegger

Authors
  1. Bernhard K Krämer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tobias Bergler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benjamin Stoelcker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siegfried Waldegger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernhard K Krämer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krämer, B., Bergler, T., Stoelcker, B. et al. Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nat Rev Nephrol 4, 38–46 (2008). https://doi.org/10.1038/ncpneph0689

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0689

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