Na+/Cl- Cotransporter

Na+/Cl- cotransporter ( sodium-chloride symporter, NCC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. The sodium-chloride symporter accounts for the absorption of 5% of the salt filtered at the glomerulus. NCC activity is known to have two control mechanisms affecting protein trafficking to the plasma membrane and transporter kinetics by phosphorylation and de-phosphorylation of conserved serine/threonine residues. Furthermore, many residues of NCC can be phosphorylated or dephosphorylated to activate or inhibit NCC uptake of Na+ and Cl-. Other NCC modulators, including intracellular chloride depletion,angiotensin II, aldosterone and vasopressin, can regulate NCC activity by phosphorylating conserved serine/threonine residues.

135-09-1
Hydroflumethiazide
135-09-1
228113-66-4
Lopixibat chloride
228113-66-4
77-36-1
Chlorthalidone
77-36-1

Background


An overview of Na+/Cl- Cotransporter

In 1990, Na+/Cl-Cotransporter (NCC) was identified by Hebert at a molecular level, belonging to solute carrier family 12. NCC, a cationic coupled chloride co-transporter protein, is encoded by SLC12A3 gene, mainly expressed in distal convoluted tubule of mammalian kidneys. NCC functions as a modulator of arterial blood pressure and as a regulator for potassium, calcium, and proton excretion. NCC is the main sodium ion resorption channel and mediates the resorption of most sodium ions in the distal convoluted tubules of the kidney. The activation of NCC has significant effect on ion balance and the regulation of blood pressure in human body.

Inhibition of Na+/Cl- Cotransporter

Several NCC inhibitors have been approved and adopted for the regulation of NCC due to the activity of NCC involved in multiple biological functions. The thiazide diuretic is a kind of well-known NCC inhibitor, which was discovered by accident and put into clinical use in 1958. In addition to NCC, thiazide diuretics also target the sodium-dependent bicarbonate-chloride cotransporter. In the treatment of hypertension, the thiazide diuretic is the first therapeutic choice for female patients, while angiotensin converting enzyme inhibitors or receptor antagonist for the majority of male patients.

Na+/Cl-Cotransporter and diseases

As mentioned above, NCC is implicated in ion balance and the regulation of blood pressure. The NCC function is demonstrated by two metabolic dysfunction syndromes caused by mutations in the SLC12A3 gene: Gitelman diseases and Gordon syndrome. Gitelman diseases are characterized by arterial hypotension, hypomagnesemia, hypocalcemia and hypokalemic metabolic alkalosis due to the functional inactivation of NCC. Gordon syndrome, also known as Pseudohypoaldosteronism type II (PHA II), is caused by the abnormal increase of NCC activity due to the lack of mutations of with-no-lysine kinases (WNK), which is characterized by hypertension, hyperkalemia and metabolic acidosis. The role of NCC in some diseases including hypertension, Gitelman diseases and Gordon syndrome has not been completely clarified yet and some interactions are still not well understood. Therefore, more researches on the function of NCC are needed in the future for the treatment of related diseases.

Reference

1. Moes, A. D., van der Lubbe, N., Zietse, R., Loffing, J., & Hoorn, E. J. (2014). The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Pflügers Archiv-European Journal of Physiology, 466(1), 107-118.

2. Wang, L., Dong, C., Xi, Y. G., & Su, X. (2015). Thiazide-sensitive Na+–Cl− cotransporter: genetic polymorphisms and human diseases. Acta biochimica et biophysica Sinica, 47(5), 325-334.

3. Gamba, G. (2012). Regulation of the renal Na+-Cl− cotransporter by phosphorylation and ubiquitylation. American Journal of Physiology-Renal Physiology, 303(12), F1573-F1583.