NKCC2, the furosemide-sensitive Na⁺-K⁺-2Cl^- cotransporter in the thick ascending limb of Henle and NCC, the thiazide-sensitive Na⁺-Cl^- cotransporter in the distal convoluted tubule, share the same activation mechanisms, consisting in the phosphorylation of conserved residues in the NH2-terminal cytosolic domain. Studies carried out in patients with hereditary forms of blood pressure alterations have helped to identify mutations in several proteins. These proteins have in common being part of the renal sodium reabsorption mechanisms. Among them, WNK kinases have been identified as regulators of NKCC2 (WNK3) and NCC (WNK1 and WNK4) activity. WNK kinases would sense changes in cell volume or intracellular chloride brought about by the NaCl transepithelial transport itself. WNK would then phosphorylate and activate kinases SPAK/OSR1, which in turn are directly responsible for phosphorylating NKCC2 and NCC. The functional association among the kinases and the transporters is further enhanced by the existance of binding domains serving for modulation of the regulatory interaction. The expression of NKCC2 and NCC in the cell apical membrane is another regulated event, though there is currently no direct link between regulation of NKCC2 or NCC membrane traffic and their phosphorylation. Disruption of these two regulatory mechanisms is involved in the physiopathology of Gordon's syndrome (pseudohypoaldosteronism type II), a monogenic low-renin form of hypertension. Long-term regulation of genetic expression of NKCC2 and NCC has also been linked to hypertension in animal models. The mechanisms for the regulation of NKCC2 and NCC are thus potential candidates as new diagnostic and therapeutic targets in hypertension.

Acknowledgements: 

Ministerio de Educación y Ciencia (BFU2007-62119)