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
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ClCKA (ClC-K1) and ClCKB (ClC-K2) are chloride channels specific to the kidney (and inner ear); Barttin is their functionally important subunit
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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
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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
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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
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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
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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
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References
Simon DB et al. (1997) Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet 17: 171–178
Matsumara M et al. (1999) Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nature Genet 21: 95–98
Birkenhäger R et al. (2001) Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29: 310–314
Schlingmann KP et al. (2004) Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350: 1314–1319
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
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
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
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
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
Waldegger S et al. (2002) Barttin increases surface expression and changes current properties of ClC-K channels. Pflügers Arch 444: 411–418
Scholl U et al. (2006) Barttin modulates trafficking and function of ClC-K channels. Proc Natl Acad Sci USA 103: 11411–11416
Uchida S et al. (1995) Localization and functional characterization of rat kidney-specific chloride channel, ClC-K1. J Clin Invest 95: 104–113
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
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
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
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
Picollo A et al. (2004) Molecular determinants of differential pore blocking of kidney CLC-K chloride channels. EMBO Rep 5: 584–589
Kobayashi K et al. (2001) Intrarenal and cellular localization of CLC-K2 protein in the mouse kidney. J Am Soc Nephrol 12: 1327–1334
Mejia R and Wade JB (2002) Immunomorphometric study of rat renal inner medulla. Am J Physiol Renal Physiol 282: F553–F557
Takeuchi Y et al. (1995) Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney. Kidney Int 48: 1497–1503
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
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
Vitzthum H et al. (2002) Nephron specific regulation of chloride channel CLC-K2 mRNA in the rat. Kidney Int 61: 547–554
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
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
Yoshikawa M et al. (1999) Localization of rat CLC-K2 chloride channel mRNA in the kidney. Am J Physiol 276: F552–F558
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
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
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
Debonneville C et al. (2001) Phosphorylation of Nedd4-2 by SGK1 regulates epithelial Na+ channel cell surface expression. EMBO J 20: 7052–7059
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
Jentsch TJ et al. (2005) Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest 115: 2039–2046
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
Carrithers SL et al. (2004) Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Kidney Int 65: 40–53
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
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
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
Rai T et al. (1999) Isolation and characterization of kidney-specific CLC-K2 chloride channel gene promoter. Biochem Biophys Res Commun 261: 432–438
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
Akizuki M et al. (2001) Impaired solute accumulation in inner medulla of Clcnk1−/− mice kidney. Am J Physiol Renal Physiol 280: F79–F87
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
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
Jeck N et al. (2000) Mutations in the chloride channel gene CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res 48: 754–758
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
Gitelman HJ et al. (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79: 221–235
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
Jeck N et al. (2004) Activating mutation of the renal epithelial chloride channel CLC-Kb predisposing to hypertension. Hypertension 43: 1175–1181
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
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
Hayama A et al. (2003) Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 119: 485–493
Jeck N et al. (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108: 1–9
Shalev H et al. (2003) The neonatal variant of Bartter syndrome and deafness: preservation of renal function. Pediatrics 112: 628–633
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.
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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
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DOI: https://doi.org/10.1038/ncpneph0689
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