WNK kinases, distal tubular ion handling and hypertension

Familial hyperkalaemic hypertension (FHH) was originally described by Paver and Pauline in 1964 [1]. Also referred to as Gordon syndrome [2] or pseudohypoaldosteronism type 2 [3], the FHH syndromes are rare autosomal dominant diseases characterized by the unusual association of low renin hypertension with hyperkalaemia and metabolic acidosis despite normal glomerular filtration rate. These clinical and biological features are the mirror image of the Gitelman syndrome. Together with the peculiar sensitivity of FHH patients to thiazide diuretics [4,5], it suggests an increased sodium reabsorption through the thiazidesensitive Na–Cl co-transporter (NCCT) as the main mechanism of the disease. Genetic analyses, however, have excluded NCCT as being directly involved in all the families studied so far, but, instead, found evidence for three loci on chromosomes 1, 17 [6] and 12 [7], and for further genetic heterogeneity [8]. More recently, the two responsible genes corresponding to the chromosome 12 and 1 loci have been identified [9]. These genes do not correspond to ionic transporters but to unexpected proteins, WNK1 and WNK4, which are two closely related members of a novel serine–threonine kinase family. Their identification paved the way for experimental and clinical studies that recently have provided important new insights into the regulatory pathways that control ion transport in the distal nephron. FHH and WNK4