Human blood pressure is controlled chronically by the kidneys, which act to regulate salt and water excretion to meet demand. Hypertension is the most common disease in the United States, affecting 35 million American. Yet most hypertension is deemed ‘essential’ (or idiopathic). We investigate mechanisms by which the kidneys regulate blood pressure, using molecular and transgenic techniques to identify novel hemodynamic pathways. A thiazide-sensitive Na-Cl cotransporter (SLC12A3) mediates NaCl transport along the distal nephron. Mutations of this gene cause Gitelman syndrome, a relatively common autosomal recessive disorder of salt wasting and hypokalemic alkalosis. We have shown that many Gitelman mutations disrupt protein folding, activating the ‘quality control’ mechanism and preventing normal protein insertion into the plasma membrane. Conversely, activation of the thiazide-sensitive Na-Cl cotransporter contributes to familial hyperkalemic hypertension (also called pseudohypoaldosteronism type 2 or Gordon’s syndrome). We have reported that members of a novel kinase family, the WNK (for With No Lysine (K)) kinases, regulate ion transport by the kidney; mutations in WNK kinases cause familial hyperkalemic hypertension. This work has identified complex interactions between kinase-sufficient and kinase-deficient (so-called ‘fractured kinases’) forms of WNK kinases that work together as molecular switches; these appear to determine whether the kidney acts to secrete potassium or to reabsorb sodium and determine the blood pressure set point. These WNK kinase actions identify potential targets for antihypertensive drug development.

Recent Publications (Pub Med)