WNK kinases and blood pressure control

Abstract

The WNK (With No K-Lysine) family of proteins is widely expressed and has been shown to promote blood pressure homeostasis through a variety of mechanisms. Members of this family have been reported to affect sodium/chloride cotransporters, sodium/potassium/chloride cotransporters, potassium/chloride cotransporters, the renal outer medullary potassium channel, and the epithelial sodium channel, directly and indirectly. Mutations in WNK1 and WNK4 were shown to cause pseudohypoaldosteronism type II, a Mendelian disorder characterized by hypertension, hyperkalemia, and acidosis. Because of the complexity of the renal system, it has been difficult to completely define the role of these kinases in kidney function. This article reviews current knowledge of the role of these proteins in ion homeostasis and volume control.

WNK1 is required for mitosis and abscission

“…These results suggest that the role of WNK1 in mitosis does not primarily account for the lethality of its deletion. In reconstitution assays, multiple WNK family members can regulate several common effectors not limited to OSR1 and SPAK (1)(2)(3)(4). In this regard, we have been unable to detect other WNKs in HeLa cells by immunoblotting.…”

“…cytokinesis | microtubules | serine-| proline-| alanine-rich kinase T he serine/threonine protein kinase WNK1 [with no lysine (K)] is important for blood pressure regulation (1)(2)(3)(4). Positional cloning identified two of the four WNK family members as the genes mutated in a form of hypertension known as pseudohypoaldosteronism type II (5).…”

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

“…In all cases examined, inhibition of ion transporters by the WNKs is due to reduced surface expression (3,7,(11)(12)(13). Figure 3, A and B, shows that this is also the case for NBCe1-B, as WNK1 KD , WNK4 KD , WNK1 , and WNK1 1-491-KD all prominently reduce surface expression of NBCe1-B (WNK1 and WNK4 had similar effects; data not shown).…”

“…Furthermore, because of the multiple roles of the WNK kinases in epithelial physiology (3,7,11,13), the finding that IRBIT is such a potent regulator of the WNK pathway likely has implications beyond fluid and electrolyte secretion in secretory glands. By reversing the inhibitory effect of the WNK/SPAK pathway, IRBIT likely has an important regulatory role in bodily volume regulation and blood pressure through regulation of renal ion transport, in acid-base regulation through regulation of HCO 3 -transporters, and in regulation of epithelial function through regulation of CFTR and NBCe1-B.…”

“…The seminal discovery that mutations in WNK1 and WNK4 are associated with hypertension (10) led to extensive characterization of their function (3,11). The kinase function of the WNKs is required for regulation of several transporters (3,11).…”