sodium chloride symporters


Summary: A subclass of symporters found in KIDNEY TUBULES, DISTAL that are the major pathway for salt resorption. Inhibition of these symporters by BENZOTHIADIAZINES is the basis of action of some DIURETICS.

Top Publications

  1. Velazquez H, Bartiss A, Bernstein P, Ellison D. Adrenal steroids stimulate thiazide-sensitive NaCl transport by rat renal distal tubules. Am J Physiol. 1996;270:F211-9 pubmed
    ..Physiological changes in circulating levels of adrenal steroids may affect renal NaCl excretion in part by regulating the rate of electroneutral Na-Cl absorption by the DCT. ..
  2. Yang S, Lo Y, Wu C, Lin S, Yeh C, Chu P, et al. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol. 2010;21:1868-77 pubmed publisher
    ..In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation. SPAK may be a promising target for antihypertensive therapy...
  3. Pacheco Alvarez D, Cristóbal P, Meade P, Moreno E, Vazquez N, Munoz E, et al. The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J Biol Chem. 2006;281:28755-63 pubmed
    ..We conclude that rNCC is activated by a mechanism that involves amino-terminal domain phosphorylation. ..
  4. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85:423-93 pubmed
  5. Kim G, Lee J, Oh Y, Chang H, Joo K, Na K, et al. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel. J Am Soc Nephrol. 2004;15:2836-43 pubmed
    ..The upregulation of AQP2 and distal renal Na(+) transporters in response to HCTZ treatment may account for the antidiuretic action of HCTZ in NDI. ..
  6. Simon D, Nelson Williams C, Bia M, Ellison D, Karet F, Molina A, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996;12:24-30 pubmed
    ..We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension. ..
  7. Melnikov S, Mayan H, Uchida S, Holtzman E, Farfel Z. Cyclosporine metabolic side effects: association with the WNK4 system. Eur J Clin Invest. 2011;41:1113-20 pubmed publisher
    ..This rise was followed by a rise in NCC protein content and pSer71 phosphorylation. These observations may explain in part the mechanism of cyclosporine-induced hypertension, hyperkalemia and hypercalciuria. ..
  8. Chiga M, Rai T, Yang S, Ohta A, Takizawa T, Sasaki S, et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008;74:1403-9 pubmed publisher
    ..These studies suggest that that the WNK-OSR1/SPAK-NCC cascade may be a novel effector system of aldosterone action in the kidney. ..
  9. Yang C, Zhu X, Ellison D. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest. 2007;117:3403-11 pubmed
    ..The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice. ..

More Information


  1. Yang S, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, et al. Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab. 2007;5:331-44 pubmed
    ..Thus, the pathogenesis of PHAII caused by a missense mutation of WNK4 was identified to be increased function of NCC through activation of the OSR1/SPAK-NCC phosphorylation cascade. ..
  2. Lalioti M, Zhang J, Volkman H, Kahle K, Hoffmann K, Toka H, et al. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet. 2006;38:1124-32 pubmed
    ..These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC...
  3. Sandberg M, Maunsbach A, McDonough A. Redistribution of distal tubule Na+-Cl- cotransporter (NCC) in response to a high-salt diet. Am J Physiol Renal Physiol. 2006;291:F503-8 pubmed
  4. Song J, Hu X, Riazi S, Tiwari S, Wade J, Ecelbarger C. Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats. Am J Physiol Renal Physiol. 2006;290:F1055-64 pubmed
    ..Overall, insulin infusion increased blood pressure, and NCC and ENaC activity in rats. Increased apical targeting of ENaC and decreased WNK4 expression may be involved. ..
  5. Beutler K, Masilamani S, Turban S, Nielsen J, Brooks H, Ageloff S, et al. Long-term regulation of ENaC expression in kidney by angiotensin II. Hypertension. 2003;41:1143-50 pubmed
    ..The results support the view that the angiotensin II receptor regulates ENaC abundance, consistent with a role for angiotensin II in regulation of collecting duct function. ..
  6. Lee D, Riquier A, Yang L, Leong P, Maunsbach A, McDonough A. Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009;296:F810-8 pubmed publisher
    ..We conclude that DCT NCC may participate in pressure natriuresis-diuresis by retraction out of apical plasma membranes and that the retraction is, at least in part, driven by the fall in ANG II that accompanies acute hypertension...
  7. Loffing J, Vallon V, Loffing Cueni D, Aregger F, Richter K, Pietri L, et al. Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome. J Am Soc Nephrol. 2004;15:2276-88 pubmed
    ..Thus, loss of NCC leads to major structural remodeling of the renal distal tubule that goes along with marked changes in glomerular and tubular function, which may explain some of the clinical features of Gitelman's syndrome. ..
  8. Richardson C, Rafiqi F, Karlsson H, Moleleki N, Vandewalle A, Campbell D, et al. Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-84 pubmed publisher
    ..They also suggest a mechanism by which increased WNK1 overexpression could lead to hypertension and that inhibitors of SPAK/OSR1 might be of use in reducing blood pressure by suppressing phosphorylation and hence activity of NCC. ..
  9. Lu C, Hilgemann D. GAT1 (GABA:Na+:Cl-) cotransport function. Kinetic studies in giant Xenopus oocyte membrane patches. J Gen Physiol. 1999;114:445-57 pubmed
    ..f) Turnover rates for reverse GAT1 transport (33 degrees C), calculated from the ratio of steady state current magnitude to total charge movement magnitude, can exceed 60 s(-1) at positive potentials. ..
  10. Yang C, Zhu X, Wang Z, Subramanya A, Ellison D. Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. J Clin Invest. 2005;115:1379-87 pubmed
    ..These findings provide insight into the complex interrelationships between WNK1 and WNK4 and provide a molecular basis for FHHt. ..
  11. Sohara E, Rai T, Yang S, Ohta A, Naito S, Chiga M, et al. Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney. PLoS ONE. 2011;6:e24277 pubmed publisher
    ..The present results demonstrated that insulin is a potent regulator of NCC phosphorylation in the kidney, and that WNK4 and SPAK are involved in this mechanism of NCC phosphorylation by insulin. ..
  12. Brooks H, Sorensen A, Terris J, Schultheis P, Lorenz J, Shull G, et al. Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics. J Physiol. 2001;530:359-66 pubmed
    ..More extensive adaptation occurred in the case of the NHE3 knockout, presumably because NHE3 is responsible for much more sodium absorption in normal mice than in NCC knockout mice. ..
  13. Belge H, Gailly P, Schwaller B, Loffing J, Debaix H, Riveira Munoz E, et al. Renal expression of parvalbumin is critical for NaCl handling and response to diuretics. Proc Natl Acad Sci U S A. 2007;104:14849-54 pubmed
    ..They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies. ..
  14. Gamba G. The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs. Am J Physiol Renal Physiol. 2009;297:F838-48 pubmed publisher
    ..Thus one of the legacies of Steve Hebert is a better understanding of salt and water homeostasis. ..
  15. Yang C, Angell J, Mitchell R, Ellison D. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003;111:1039-45 pubmed
    ..Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis. ..
  16. Lu C, Hilgemann D. GAT1 (GABA:Na+:Cl-) cotransport function. Steady state studies in giant Xenopus oocyte membrane patches. J Gen Physiol. 1999;114:429-44 pubmed
    ..The slopes of current-voltage relations change only little when current is reduced four- to eightfold by lowering each cosubstrate concentration; they increase twofold upon addition of 100 mM Na+ to the extracellular (pipette) side. ..
  17. San Cristobal P, Pacheco Alvarez D, Richardson C, Ring A, Vazquez N, Rafiqi F, et al. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc Natl Acad Sci U S A. 2009;106:4384-9 pubmed publisher
    ..These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K(+) secretion. ..
  18. Sandberg M, Riquier A, Pihakaski Maunsbach K, McDonough A, Maunsbach A. ANG II provokes acute trafficking of distal tubule Na+-Cl(-) cotransporter to apical membrane. Am J Physiol Renal Physiol. 2007;293:F662-9 pubmed
  19. Hilgemann D, Lu C. GAT1 (GABA:Na+:Cl-) cotransport function. Database reconstruction with an alternating access model. J Gen Physiol. 1999;114:459-75 pubmed
  20. Rozansky D, Cornwall T, Subramanya A, Rogers S, Yang Y, David L, et al. Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. J Clin Invest. 2009;119:2601-12 pubmed publisher
    ..These data thus delineate what we believe to be a novel mechanism for aldosterone activation of NCC through SGK1 signaling of WNK4 kinase. ..
  21. Monroy A, Plata C, Hebert S, Gamba G. Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol. 2000;279:F161-9 pubmed
    ..Both ion binding sites alter thiazide-mediated inhibition of transport, indicating that the thiazide-binding site is either shared or modified by both Na(+) and Cl(-). ..
  22. van der Lubbe N, Lim C, Fenton R, Meima M, Jan Danser A, Zietse R, et al. Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. Kidney Int. 2011;79:66-76 pubmed publisher
    ..These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension. ..
  23. Schultheis P, Lorenz J, Meneton P, Nieman M, Riddle T, Flagella M, et al. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule. J Biol Chem. 1998;273:29150-5 pubmed
    ..These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome. ..
  24. Frindt G, Palmer L. Effects of dietary K on cell-surface expression of renal ion channels and transporters. Am J Physiol Renal Physiol. 2010;299:F890-7 pubmed publisher
  25. Hu D, Burtner C, Hong A, Lobo P, Okusa M. Correction of renal hypertension after kidney transplantation from a donor with Gitelman syndrome. Am J Med Sci. 2006;331:105-9 pubmed
    ..Furthermore, this case suggests the potential use of thiazide diuretics in the treatment of calcineurin-induced hypertension...
  26. Hoorn E, Walsh S, McCormick J, Fürstenberg A, Yang C, Roeschel T, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011;17:1304-9 pubmed publisher
  27. Kim S, Wang W, Nielsen J, Praetorius J, Kwon T, Knepper M, et al. Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol. 2004;286:F922-35 pubmed
    ..The decreased abundance of NHE3, BSC-1, TSC, and Na-K-ATPase may play a compensatory role to promote sodium excretion. ..
  28. Esteva Font C, Wang X, Ars E, Guillen Gomez E, Sans L, González Saavedra I, et al. Are sodium transporters in urinary exosomes reliable markers of tubular sodium reabsorption in hypertensive patients?. Nephron Physiol. 2010;114:p25-34 pubmed publisher
    ..Our results do not support the idea that excretion levels of NKCC2 and NCC via urinary exosomes are markers of tubular sodium reabsorption in hypertensive patients. ..
  29. Louis Dit Picard H, Barc J, Trujillano D, Miserey Lenkei S, Bouatia Naji N, Pylypenko O, et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012;44:456-60, S1-3 pubmed publisher
    ..Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure...
  30. Zaarour N, Demaretz S, Defontaine N, Zhu Y, Laghmani K. Multiple evolutionarily conserved Di-leucine like motifs in the carboxyl terminus control the anterograde trafficking of NKCC2. J Biol Chem. 2012;287:42642-53 pubmed publisher
    ..Based upon these data, we propose abnormal anterograde trafficking as a common mechanism associated with mutations depriving NKCC2, and also all other members of the SLC12A family, of their COOH terminus. ..
  31. Meij I, van den Heuvel L, Hemmes S, Van Der Vliet W, Willems J, Monnens L, et al. Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss. Nephrol Dial Transplant. 2003;18:512-6 pubmed
    ..In addition, haplotype analysis excluded linkage to the FXYD2 region on chromosome 11q23. Our results indicate that, in addition to the currently known loci involved in renal Mg(2+) handling, at least one other gene must be involved. ..
  32. Akiyama K, Miyashita T, Mori T, Inamoto R, Mori N. Expression of thiazide-sensitive Na+-Cl- cotransporter in the rat endolymphatic sac. Biochem Biophys Res Commun. 2008;371:649-53 pubmed publisher
    ..These analyses indicated that TSC genes and proteins were expressed in the rat ES. In contrast, it was not observed in the rat cochlea by RT-PCR. This is the first report confirming the expression of TSC in the ES. ..
  33. An C, Liang J, Zhang K, Su X. Polymorphisms in the SLC12A3 Gene Encoding Sodium-Chloride Cotransporter are Associated with Hypertension: A Family-Based Study in the Mongolian Population. Kidney Blood Press Res. 2016;41:18-28 pubmed publisher
    ..05). These results suggest that SNPs in the SLC12A3 gene confer susceptibility to hypertension in the Mongolian population. Further research is needed to validate the functional role of SLC12A3 polymorphisms in hypertension. ..
  34. Capasso G, Rizzo M, Garavaglia M, Trepiccione F, Zacchia M, Mugione A, et al. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol. 2008;295:F556-67 pubmed publisher
    ..17 +/- 0.59 (n = 23) in MHS rats (P < 0.05). The data indicate that, in salt-sensitive hypertension, there is a strong upregulation, both of NCC and ClC-K along the DCT, which explains the persistence of hypertension...
  35. Chávez Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco Alvarez D, Vidal Petiot E, et al. WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension. 2014;64:1047-53 pubmed publisher
    ..In conclusion, WNK kinases form a network in which WNK4 associates with WNK1 and WNK3 to regulate NCC. ..
  36. Saritas T, Borschewski A, McCormick J, Paliege A, Dathe C, Uchida S, et al. SPAK differentially mediates vasopressin effects on sodium cotransporters. J Am Soc Nephrol. 2013;24:407-18 pubmed publisher
    ..In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron. ..
  37. Laverty G, Elbrønd V, Arnason S, Skadhauge E. Endocrine regulation of ion transport in the avian lower intestine. Gen Comp Endocrinol. 2006;147:70-7 pubmed
    ..Recent findings suggesting effects of other hormones on lower intestinal transport are also presented...
  38. Ecelbarger C, Tiwari S. Sodium transporters in the distal nephron and disease implications. Curr Hypertens Rep. 2006;8:158-65 pubmed
  39. Chee K, Vorontsova I, Lim J, Kistler J, Donaldson P. Expression of the sodium potassium chloride cotransporter (NKCC1) and sodium chloride cotransporter (NCC) and their effects on rat lens transparency. Mol Vis. 2010;16:800-12 pubmed
    ..To characterize the expression patterns of the Na+-K+-Cl(-) cotransporter (NKCC) 1 and NKCC2, and the Na+-Cl(-) cotransporter (NCC) in the rat lens and to determine if they play a role in regulating lens volume and transparency...
  40. Ko B, Hoover R. Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter. Curr Opin Nephrol Hypertens. 2009;18:421-7 pubmed publisher
    ..NCC is subject to a complex regulatory network of kinases, which appear quite sensitive to alterations of the hormonal and physiologic milieu. ..
  41. Zhai X, Kristoffersen I, Christensen E. Immunocytochemistry of renal membrane proteins on epoxy sections. Kidney Int. 2007;72:731-5 pubmed
    ..The advantages of our novel method include not only enhanced morphological quality but also the feasibility for investigators to visualize antigens of interest using archival specimens in Epon blocks. ..
  42. Nishiyama K, Tanaka Y, Nakajima K, Mokubo A, Atsumi Y, Matsuoka K, et al. Polymorphism of the solute carrier family 12 (sodium/chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitud. Diabetologia. 2005;48:1335-8 pubmed
    ..043 and 0.022, respectively). The SLC12A3 +78A(+) genotype may have a protective effect against the development and/or progression of diabetic nephropathy in Japanese type 2 diabetic patients. ..
  43. Yang S, Yamauchi K, Rai T, Hiyama A, Sohara E, Suzuki T, et al. Regulation of apical localization of the thiazide-sensitive NaCl cotransporter by WNK4 in polarized epithelial cells. Biochem Biophys Res Commun. 2005;330:410-4 pubmed
    ..The regulation of intracellular localization of NCC by WNK4 might not be involved in the pathogenesis of PHAII. ..
  44. Peters M, Jeck N, Reinalter S, Leonhardt A, Tönshoff B, Klaus G G, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med. 2002;112:183-90 pubmed
    ..The aim of this study was to characterize the clinical features associated with each mutation in a large cohort of genetically defined patients...
  45. Masilamani S, Wang X, Kim G, Brooks H, Nielsen J, Nielsen S, et al. Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction. Am J Physiol Renal Physiol. 2002;283:F648-57 pubmed
  46. van der Lubbe N, Zietse R, Hoorn E. Effects of angiotensin II on kinase-mediated sodium and potassium transport in the distal nephron. Curr Opin Nephrol Hypertens. 2013;22:120-6 pubmed publisher
    ..Pathophysiologically, Ang-II-induced activation of NCC appears to contribute to salt-sensitive hypertension. ..
  47. Breves J, Serizier S, Goffin V, McCormick S, Karlstrom R. Prolactin regulates transcription of the ion uptake Na+/Cl- cotransporter (ncc) gene in zebrafish gill. Mol Cell Endocrinol. 2013;369:98-106 pubmed publisher
    ..These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl(-) uptake in zebrafish for the first time. ..
  48. Hayashi M. [Bartter syndrome and Gitelman syndrome]. Nihon Naika Gakkai Zasshi. 2006;95:877-81 pubmed
  49. Bonnet U, Leniger T, Wiemann M. Alteration of intracellular pH and activity of CA3-pyramidal cells in guinea pig hippocampal slices by inhibition of transmembrane acid extrusion. Brain Res. 2000;872:116-24 pubmed
  50. Kwon T, Frøkiaer J, Han J, Knepper M, Nielsen S. Decreased abundance of major Na(+) transporters in kidneys of rats with ischemia-induced acute renal failure. Am J Physiol Renal Physiol. 2000;278:F925-39 pubmed
    ..We conclude that reduced levels of Na transporters along the nephron may play a critical role in the impairment of tubular Na reabsorption, and hence increased Na excretion, in ischemia-induced ARF. ..
  51. Beaumont K, Vaughn D, Casto R, Printz M, Fanestil D. Thiazide diuretic receptors in spontaneously hypertensive rats and 2-kidney 1-clip hypertensive rats. Clin Exp Hypertens A. 1990;12:215-26 pubmed
    ..This increase may reflect altered hormonal or ionic input to the distal tubule and may contribute to elevated sodium reabsorption in this segment in the SHR. ..
  52. Mercier Zuber A, O Shaughnessy K. Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Curr Opin Nephrol Hypertens. 2011;20:534-40 pubmed publisher
    ..In vivo, SPAK plays a major role in the regulation of blood pressure and represents a potential target for the development of novel diuretics. ..
  53. Vidotti D, Arnoni C, Maquigussa E, Boim M. Effect of long-term type 1 diabetes on renal sodium and water transporters in rats. Am J Nephrol. 2008;28:107-14 pubmed
    ..The decrease of alpha-ENaC in D animals may compensate for the increased sodium reabsorption via SGLT1 resulting in discrete natriuresis. DM-induced polyuria was not due to changes in AQP2 expression. ..