Sorting out Lysosomal Trafficking of the Thiazide-Sensitive Na-Cl Co-transporter

Abstract

The aldosterone-sensitive distal nephron is a key site for regulated renal sodium reabsorption and, hence, plays a critical role in the long-term control of arterial BP and extracellular fluid volume. Coupled Na+ and Cl− transport across the luminal surface of the most proximal portion of the aldosterone-sensitive distal nephron, the distal convoluted tubule, occurs through the thiazide-sensitive Na-Cl co-transporter (NCC). NCC bears a similar structure to other members of the SLC12 family of electroneutral cation chloride co-transporters, containing 12 transmembrane domains flanked by large cytoplasmic amino and carboxyl termini and two sites for N-linked glycosylation.1 It exists functionally as a homodimer at the apical surface of the distal convoluted tubule, where it reabsorbs 5 to 10% of the filtered sodium chloride load.1 NCC is the molecular target of thiazides and thiazide-like diuretics, which, because of their cardiovascular benefits, are recommended first-line agents for patients with newly diagnosed essential hypertension. Given the relevance of NCC function in human hypertension, it is not surprising that the co-transporter has become the subject of intense investigation in recent years. The greatest impetus that stimulated the recent explosion of NCC research is the seminal discovery in 2001 that familial hyperkalemic hypertension (FHHt; also known as PHA-2, or Gordon syndrome), a Mendelian syndrome of NCC overactivity, is caused by mutations in the with-no-lysine (WNK) …