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Gene Review

Slc12a3  -  solute carrier family 12 (sodium/chloride...

Rattus norvegicus

Synonyms: NCC, Na-Cl symporter, Solute carrier family 12 member 3, TSC, Thiazide-sensitive sodium-chloride cotransporter, ...
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Disease relevance of Slc12a3

  • Increased renal alpha-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape [1].
  • Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC) [2].
  • Upregulation of renal BSC1 and TSC in prenatally programmed hypertension [3].
  • Previously, we showed an increase in the whole kidney abundance of aldosterone-sensitive proteins, the alpha- and gamma (70-kDa-band)-subunits of the epithelial Na(+) channel (ENaC), and the thiazide-sensitive Na-Cl cotransporter (NCC) in our rat model of SIADH [4].
  • In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na(+) transporters do not participate in the development of Li-induced polyuria [5].

Psychiatry related information on Slc12a3

  • To avoid a possible confound between the effects of sleep loss and disturbed circadian rhythms in previous studies of total sleep deprivation (TSD) by the disk-over-water method, TSD rats and their yoked control (TSC) rats had been maintained in constant light both before and during the experiment [6].

High impact information on Slc12a3

  • The analysis revealed that the renal abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) was profoundly and selectively decreased [7].
  • Immunocytochemistry showed a strong decrease in NCC labeling in distal convoluted tubules of aldosterone-escape rats with no change in the cellular distribution of NCC [7].
  • Thus, we determined the effect of ovariectomy (OVX) and estrogen replacement on the ultrastructural localization of TSC in rat kidney using immunocytochemistry [8].
  • Furthermore, 7-day treatment of rats with an orally administered mineralocorticoid, fludrocortisone, increased TSC expression (656 +/- 114% of controls) [9].
  • The thiazide-sensitive Na+-Cl- cotransporter (NCC) is the major pathway for salt reabsorption in the distal convoluted tubule, serves as a receptor for thiazide-type diuretics, and is involved in inherited diseases associated with abnormal blood pressure [10].

Chemical compound and disease context of Slc12a3


Biological context of Slc12a3

  • The transcription regulatory region of the TSC gene confers DCT-specific gene expression [16].
  • The TSC gene was localized to chromosome 19p12-14 [16].
  • Immunohistochemical analysis clearly showed that LacZ gene expression was co-localized to distal convoluted tubules (DCT) with TSC, indicating that the 5'FL/rTSC regulates the renal tubule-specific TSC expression [16].
  • These data indicate that, in MHS rats, there is a strong upregulation of NKCC2 along the TAL associated with increased GFR, robust inhibition of NCC cotransporter along the DCT and modest downregulation of alpha-ENaC along the CD [17].
  • These results point to early regulatory processes that decrease renal Na excretion without an increase in the abundance of any Na transporter, followed by a late aldosterone-dependent response associated with upregulation of NCC and ENaC [18].

Anatomical context of Slc12a3

  • Functional expression of cotransporters in Xenopus laevis oocytes revealed that the mutants displayed drastically decreased thiazide-sensitive (22)Na(+) uptake compared with wild-type NCC [19].
  • The mechanism of T cell tolerance to the hydroxylated CII epitope in TSC mice was found to involve intrathymic deletion and induction of peripheral tolerance [20].
  • We demonstrated the presence of the NCC transporter in the rat small intestine (ileum and jejunum) and human HT-29 cells, by using reverse transcription-PCR, Northern blot, Western blot, and immunofluorescence [21].
  • In the present study, some characteristics of unloaded shortening during the SC and its effect on a subsequent, electrically triggered twitch (Tsc) were examined at a sarcomere level in isolated rat myocytes [22].
  • In conclusion, a HS diet provokes a rapid and persistent redistribution of NCC from apical to subapical membranes, a mechanism that would facilitate a homeostatic decrease in NaCl reabsorption in the DCT to compensate for increased dietary salt [23].

Associations of Slc12a3 with chemical compounds

  • The molecular mechanism underlying the renal expression localization of the thiazide-sensitive Na-Cl cotransporter (TSC) gene was studied [16].
  • However, NO synthase inhibition did not block the decrease in NCC abundance normally seen with aldosterone escape [24].
  • BUO resulted in downregulation of type 3 Na+/H+ exchanger (NHE3) to 41 +/- 14%, type 2 Na-Pi cotransporter (NaPi-2) to 26 +/- 6%, Na-K-ATPase to 67 +/- 8%, type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) to 20 +/- 7%, and thiazide-sensitive cotransporter (TSC) to 37 +/- 9% [25].
  • Fractional sodium excretion (FE(Na)) and plasma potassium levels were markedly increased, and the expressions of the cortical type 3 Na(+)/H(+) exchanger (NHE3), thiazide-sensitive Na-Cl cotransporter (NCC), and Na-K-ATPase were significantly decreased in response to DDAVP and candesartan cotreatment [26].
  • In contrast, interchanging transmembrane regions between rat and flounder NCC revealed that affinity-modifying residues for chloride are located within the transmembrane 1-7 region and for thiazides are located within the transmembrane 8-12 region, whereas both segments seem to be implicated in defining sodium affinity [10].

Other interactions of Slc12a3


Analytical, diagnostic and therapeutic context of Slc12a3

  • The densitometry of immunoblots for NCC, alpha- and gamma-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161 [1].
  • Subcellular localization of ENaC subunits and NCC were analysed by immunohistochemistry [2].
  • Renal protein content of ENaC subunits, ubiquitin-protein-ligase Nedd4-2 and NaCl cotransporter (NCC) were assessed by western blot [2].
  • Semiquantitative immunoblotting revealed that the abundance of BSC-1 (57%) and TSC (46%) were profoundly decreased in the inner stripe of the outer medulla (ISOM) and cortex/outer stripe of the outer medulla (OSOM), respectively [27].
  • Determination of specific mRNA levels by ELISA-linked RT-PCR revealed a significantly increased BSC1 mRNA at 1 day (P < 0.01), 4 wk (P < 0.01), and 8 wk (P < 0.001) of age, and a significantly increased TSC mRNA at 4 wk of age (P < 0.05) in the experimental group [3].


  1. Increased renal alpha-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape. Tiwari, S., Packer, R.K., Hu, X., Sugimura, Y., Verbalis, J.G., Ecelbarger, C.A. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  2. Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC). Yu, Z., Serra, A., Sauter, D., Loffing, J., Ackermann, D., Frey, F.J., Frey, B.M., Vogt, B. Nephrol. Dial. Transplant. (2005) [Pubmed]
  3. Upregulation of renal BSC1 and TSC in prenatally programmed hypertension. Manning, J., Beutler, K., Knepper, M.A., Vehaskari, V.M. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  4. Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape. Song, J., Hu, X., Khan, O., Tian, Y., Verbalis, J.G., Ecelbarger, C.A. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  5. Altered expression of renal AQPs and Na(+) transporters in rats with lithium-induced NDI. Kwon, T.H., Laursen, U.H., Marples, D., Maunsbach, A.B., Knepper, M.A., Frokiaer, J., Nielsen, S. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  6. Sleep deprivation in the rat: XVI. Effects in a light-dark cycle. Tsai, L.L., Bergmann, B.M., Rechtschaffen, A. Sleep. (1992) [Pubmed]
  7. The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon. Wang, X.Y., Masilamani, S., Nielsen, J., Kwon, T.H., Brooks, H.L., Nielsen, S., Knepper, M.A. J. Clin. Invest. (2001) [Pubmed]
  8. Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. Verlander, J.W., Tran, T.M., Zhang, L., Kaplan, M.R., Hebert, S.C. J. Clin. Invest. (1998) [Pubmed]
  9. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Kim, G.H., Masilamani, S., Turner, R., Mitchell, C., Wade, J.B., Knepper, M.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  10. Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding. Moreno, E., Cristóbal, P.S., Rivera, M., Vázquez, N., Bobadilla, N.A., Gamba, G. J. Biol. Chem. (2006) [Pubmed]
  11. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. Moriguchi, T., Urushiyama, S., Hisamoto, N., Iemura, S., Uchida, S., Natsume, T., Matsumoto, K., Shibuya, H. J. Biol. Chem. (2005) [Pubmed]
  12. Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats. Song, J., Hu, X., Riazi, S., Tiwari, S., Wade, J.B., Ecelbarger, C.A. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  13. A novel fluid resuscitation therapy for hemorrhagic shock. Roy, J.W., Graham, M.C., Griffin, A.M., Gainer, J.L. Shock (1998) [Pubmed]
  14. The effect of trans sodium crocetinate (TSC) in a rat oleic acid model of acute lung injury. Gainer, J.L., Stennett, A.K., Murray, R.J. Pulmonary pharmacology & therapeutics. (2005) [Pubmed]
  15. Trans-sodium crocetinate does not affect oxygen uptake in rats during treadmill running. Kemi, O.J., Ellingsen, O. Scand. J. Clin. Lab. Invest. (2005) [Pubmed]
  16. Renal tubule-specific transcription and chromosomal localization of rat thiazide-sensitive Na-Cl cotransporter gene. Taniyama, Y., Sato, K., Sugawara, A., Uruno, A., Ikeda, Y., Kudo, M., Ito, S., Takeuchi, K. J. Biol. Chem. (2001) [Pubmed]
  17. Altered expression of renal apical plasma membrane Na+ transporters in the early phase of genetic hypertension. Capasso, G., Rizzo, M., Evangelista, C., Ferrari, P., Geelen, G., Lang, F., Bianchi, G. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  18. Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction. Masilamani, S., Wang, X., Kim, G.H., Brooks, H., Nielsen, J., Nielsen, S., Nakamura, K., Stokes, J.B., Knepper, M.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  19. N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter. Hoover, R.S., Poch, E., Monroy, A., Vázquez, N., Nishio, T., Gamba, G., Hebert, S.C. J. Am. Soc. Nephrol. (2003) [Pubmed]
  20. A transient post-translationally modified form of cartilage type II collagen is ignored by self-reactive T cells. Yamada, H., Dzhambazov, B., Bockermann, R., Blom, T., Holmdahl, R. J. Immunol. (2004) [Pubmed]
  21. Thiazide-sensitive NaCl-cotransporter in the intestine: possible role of hydrochlorothiazide in the intestinal Ca2+ uptake. Bazzini, C., Vezzoli, V., Sironi, C., Dossena, S., Ravasio, A., De Biasi, S., Garavaglia, M., Rodighiero, S., Meyer, G., Fascio, U., Fürst, J., Ritter, M., Bottà, G., Paulmichl, M. J. Biol. Chem. (2005) [Pubmed]
  22. Sarcomere dynamics in a spontaneous contraction wave and its effect on the following, electrically triggered twitch in rat myocyte. Comparison with the rested state twitch. Tameyasu, T., Kasugai, H., Tanaka, M., Harada, H. J. Gen. Physiol. (1994) [Pubmed]
  23. Redistribution of distal tubule Na+-Cl- cotransporter (NCC) in response to a high-salt diet. Sandberg, M.B., Maunsbach, A.B., McDonough, A.A. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  24. Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO. Turban, S., Wang, X.Y., Knepper, M.A. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  25. Altered expression of major renal Na transporters in rats with bilateral ureteral obstruction and release of obstruction. Li, C., Wang, W., Kwon, T.H., Knepper, M.A., Nielsen, S., Frøkiaer, J. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  26. Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats. Kwon, T.H., Nielsen, J., Knepper, M.A., Frøkiaer, J., Nielsen, S. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  27. Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats. Elkjaer, M.L., Kwon, T.H., Wang, W., Nielsen, J., Knepper, M.A., Frøkiaer, J., Nielsen, S. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
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