Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation

Major advances are being made in identifying the structure and behaviour of regulatory cascades that control the activity of cation–Cl⁻ cotransporters and certain Na⁺, K⁺ and Cl⁻ channels. These transporters play key roles in regulating arterial blood pressure as they are not only responsible for NaCl reabsorption in the thick ascending limb and distal tubule of the kidney, but are also involved in regulating smooth muscle Ca²⁺ levels. It is now apparent that defects in these transporters, and particularly in the regulatory cascades, cause some monogenetic forms of hypertension and may contribute to essential hypertension and problems with K⁺ homoeostasis. Two families of kinases are prominent in these processes: the Ste-20-related kinases [OSR1 (oxidative stress-responsive kinase 1) and SPAK (Ste20/SPS1-related proline/alanine-rich kinase)] and the WNKs [with no lysine kinases]. These kinases affect the behaviour of their targets through both phosphorylation and by acting as scaffolding proteins, bringing together regulatory complexes. This review analyses how these kinases affect transport by activating or inhibiting individual transporters at the cell surface, or by changing the surface density of transporters by altering the rate of insertion or removal of transporters from the cell surface, and perhaps through controlling the rate of transporter degradation. This new knowledge should not only help us target antihypertensive therapy more appropriately, but could also provide the basis for developing new therapeutic approaches to essential hypertension.