Extrarenal roles of the with‐no‐lysine[K] kinases (WNKs)

Abstract

Summary Identified over a decade ago, the with‐no‐lysine[K] kinases (WNKs) have been the subsequent focus of intense research into the renal handling of Na+, Cl− and K+ and several rare monogenetic diseases. However, the potential extrarenal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca2+ and PO43− homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggest a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels, including the vascular resistance vessels, where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel 3 and/or phosphorylation of the Na+−K+−2Cl− cotransporter 1 in vascular smooth muscle cells. The WNKs and many of the cation‐coupled Cl− cotransporters they regulate are highly expressed in the central nervous system and recent work suggests that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy Type 2. Finally, the WNK–sterile 20 kinase signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis, but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation.

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

“…WNK1 controls endothelial cells by mechanisms including the regulation of several transcription factors, such as Slug, ZEB-1, and β-catenin, which have far-reaching roles in disease. WNK1 is mutated in PHAII, and although research focus has been on the impact on kidney function, many patients exhibit cardiovascular disorders (24,25). The detailed mechanisms by which WNK1 regulates the cardiovascular system need to be further elucidated, as they may provide a basis for targeting WNK1 functions in disease.…”

“…The WNK1 angiogenic and cardiac defects are phenocopied by global or endothelial-specific OSR1 deletion, and can be rescued by expressing an endothelial-specific constitutively active OSR1 (21). PHAII patients regularly manifest cardiovascular symptoms (24,25); however, effects of WNK mutations on these symptoms have not been analyzed.…”

Hypertension: the missing WNKs

“…Another example of kinase-independent WNK functions involves the control of SGK1 activation, which then results in SGK1-dependent inhibition of Nedd4-2 activity to block ubiquitination and internalization of the epithelial Na ϩ channel (ENaC) (57,75,176). While the focus has centered on the role of this pathway in the kidney, more recent studies have looked at WNK functions in extrarenal tissues (142), most notably the cardiovascular system (see below).…”

“…The impact of WNKs on the vasculature is multifaceted, with a current major focus of study on the canonical signaling to OSR1/SPAK and regulation of amount, activity, and localization of ion cotransporters and channels that play a major role in vascular contractility and blood pressure control. However, emerging evidence suggests that WNKs may have vascular roles independently of SPAK/OSR1 signaling, both kinase dependent and independent (21,76,142). These may include effects on angiogenic sprouting and vessel development and organization, with WNKs regulating transcription factors, splicing factors, and other signaling mediators that can affect vessel integrity and functions (21,80).…”

With no lysine L-WNK1 isoforms are negative regulators of the K+-Cl− cotransporters

“…In regard to full-length WNK1 (L-WNK1), this kinase has been related to renal ion transport and neuronal chloride concentration (5,34,66). Mutations in this gene cause two different diseases in humans: a form of salt-sensitive hypertension known as pseudohypoaldosteronism type II (PHAII) or familial hyperkalemic hypertension (65) and hereditary sensory neuropathy type 2 (HSN2), a recessive disorder in which peripheral sensory nerves and, therefore, sensitivity are lost (29,55,56,59). Thus L-WNK1 kinase, which is ubiquitously expressed, is expected to be a modulator in the SLC12 family of cotransporters.…”