Hypertension: the missing WNKs

Abstract

The With no Lysine [K] (WNK) family of enzymes are central in the regulation of blood pressure. WNKs have been implicated in hereditary hypertension disorders, mainly through control of the activity and levels of ion cotransporters and channels. Actions of WNKs in the kidney have been heavily investigated, and recent studies have provided insight into not only the regulation of these enzymes but also how mutations in WNKs and their interacting partners contribute to hypertensive disorders. Defining the roles of WNKs in the cardiovascular system will provide clues about additional mechanisms by which WNKs can regulate blood pressure. This review summarizes recent developments in the regulation of the WNK signaling cascade and its role in regulation of blood pressure.

Keywords: WNK; cardiovascular; hypertension.

Fig. 1.

Complexity in regulation of With no Lysine [K] (WNK) levels and activity. The regulation of WNK signaling occurs through several mechanism, with the canonical hyper- or hypotonic stress-mediated activation of OSR1/SPAK and regulation of ion cotransporters (top left) being extensively studied. Recent data have shown other regulatory mechanisms, with KLHL2/3-cullin3 ubiquitinating (ub) WNKs and controlling their levels and degradation (top right), regulation of WNK localization in the cell with an uncharacterized cytoplasmic/vesicular distribution that is altered upon osmotic stress (bottom left), and finally WNK oligomerization (bottom right) controls activity in a positive fashion via reciprocal activation or negative inhibition mediated by the autoinhibitory (AI) domain.

Fig. 2.

WNKs in the vasculature. Both endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in blood vessels predominantly express WNK1 and WNK3, with WNK1 being the major isoform in ECs while both isoforms are expressed to similar levels in VSMCs but play different roles (187). Both WNK1 and WNK3 can regulate multiple ion cotransporters and channels, as well as various signaling pathways that control vascular contractility, which contributes to blood pressure. The pathways presented here include defined WNK functions in the vasculature, as well as hypothesized pathways based on the expression of the ion cotransporters and channels in the ECs and VSMCs, coupled with previously characterized WNK interactions and signaling and known functions of these ion cotransporters and channels in the vasculature. See the text for additional definitions.