WNK1

WNK1 is a serine/threonine kinase that regulates ion balance by activating SPAK/OSR1 signaling, which phosphorylates cation-chloride cotransporters including NKCC1, NKCC2, and NCC^[1]. Mechanistically, WNK1 and WNK4 phosphorylate and activate SPAK/OSR1, placing WNK1 within a conserved WNK-SPAK/OSR1 transporter-control pathway^[2]. In disease models, WNK1 or WNK4 mutations cause pseudohypoaldosteronism type II/familial hyperkalemic hypertension, linking pathway activation to renal salt handling, hyperkalemia, and hypertension^[3]. Compared with WNK4, WNK1-driven familial hyperkalemic hypertension remains SPAK-dependent but shows different distal-nephron effects on NCC abundance and phosphorylation^[4]. For experimental applications, WNK463 provides a pan-WNK inhibitor tool that affects cardiovascular, renal, blood-pressure, fluid, and electrolyte phenotypes in rodent hypertension models^[5].

References:

[1]. Moriguchi T, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem. 2005 Dec 30;280(52):42685-93. [Content Brief]

[2]. Vitari AC, et al. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J. 2005 Oct 1;391(Pt 1):17-24. [Content Brief]

[3]. Wilson FH, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001 Aug 10;293(5532):1107-12. [Content Brief]

[4]. Rafael C, et al. Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4. Sci Rep. 2018 Feb 19;8(1):3249. [Content Brief]

[5]. Yamada K, et al. Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016 Nov;12(11):896-898. [Content Brief]

WNK1 Inhibitor (1)

WNK1 Related Products (1):

Cat. No.	Product Name	Effect	Purity

HY-100626

WNK463	Inhibitor	99.75%
WNK463 is an orally bioavailable pan-With-No-Lysine (K) (WNK)-kinase inhibitor with IC_50s of 5 nM, 1 nM, 6 nM, and 9 nM for WNK1, WNK2, WNK3, and WNK4, respectively.

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