The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs

Abstract

The thiazide-sensitive Na+-Cl(-) cotransporter is the major salt reabsorption pathway in the distal convoluted tubule, which is located just after the macula densa at the beginning of the aldosterone-sensitive nephron. This cotransporter was identified at the molecular level in the early 1990s by the pioneering work of Steven C. Hebert and coworkers, opening the molecular area, not only for the Na+-Cl(-) cotransporter but also for the family of electroneutral cation-coupled chloride cotransporters that includes the loop diuretic-sensitive Na+-K+-2Cl(-) cotransporter of the thick ascending limb of Henle's loop. This work honoring the memory of Steve Hebert presents a brief review of our current knowledge about salt and water homeostasis generated as a consequence of cloning the cotransporter, with particular emphasis on the molecular biology, physiological properties, human disease due to decreased or increased activity of the cotransporter, and regulation of the cotransporter by a family of serine/threonine kinases known as WNK. Thus one of the legacies of Steve Hebert is a better understanding of salt and water homeostasis.

Fig. 1.

Salt reabsorption pathways at the beginning of the aldosterone-sensitive distal nephron. NCC, Na⁺-Cl⁻ cotransporter. ENaC, epithelial sodium channel. DCT, distal convoluted tubule; CNT, connecting tubule. Inset: mechanisms for salt and calcium reabsorption in DCT1. Arrow shows macula densa.

Fig. 2.

Structure-function relationship model for NCC [from Moreno et al. (69)].

Fig. 3.

Model for ANG II modulation of WNK4-SPAK-NCC interaction in normovolemia (A), in hypovolemia (B), and in patients with PHAII type mutations (C) [from San Cristobal et al. (95)].