Role of WNK kinases in blood pressure control

With-No-Lysine [K] (WNK) kinases are a group of serine/threonine protein kinases with an unusual location of the catalytic lysine. There are four mammalian WNK kinases, WNK1-4, each encoded by a separate gene. In addition, WNK1 has two alternatively spliced isoforms: a ubiquitously expressed full-length long isoform (L-WNK1) with kinase activity and a kidney-specific isoform (KS-WNK1) lacking kinase activity. Mutations of WNK1 and WNK4 genes cause a genetic hypertension syndrome, pseudohypoaldosteronism type 2 (PHA2). Recent studies show that WNK1, 3 and 4 are expressed in the aldosterone-sensitive distal tubules of kidney and contribute to sodium (Na⁺) and potassium (K⁺) homeostasis by regulating tubular Na⁺ and K^- transporters in complex manners. Mice with heterozygous disruption of WNK1 gene have hypotension but without apparent renal Na^- wasting. L-WNK1 is also expressed in heart and blood vessel. Thus, function of WNK1 in cardiovascular system may also contribute to blood pressure regulation. Transgenic or knockin mice carrying a disease-causing WNK4 gene exhibit typical phenotypes of PHA2 by increasing renal Na^- reabsorption. The review summarizes recent studies on the mechanism of WNK/kinases regulation of Na⁺ homeostasis and cardiovascular function and the role in blood pressure control.