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(Circulation. 2005;112:3371-3372.)
© 2005 American Heart Association, Inc.

Editorial

Association of Blood Pressure With Genetic Variation in WNK Kinases in a White European Population

Haifeng Zhang, MD; Jan A. Staessen, MD, PhD

From the Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium (H.Z., J.A.S.), and the Department of Cardiology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China (H.Z.).

Correspondence to Jan A. Staessen, Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail jan.staesssen@med.kuleuven.be

Key Words: Editorials • cardiovascular diseases • hypertension • genetics • blood pressure

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Mutations in a recently discovered family of protein kinases are responsible for an autosomal-dominant form of inherited hypertension, known as Gordon’s syndrome or pseudohypoaldosteronism type II (PHAII).¹ The phenotype also includes hyperkalemia and hyperchloremic metabolic acidosis.¹ The name of this kinase family is WNK (with no lysine [K]) because of the absence of a lysine in subdomain II of the enzymes.² WNK1 and WNK4, located in human chromosomes 12 and 17, respectively, are predominantly expressed in the distal convoluted tubules and the collecting ducts of the kidney.¹

Article p 3423

In vitro, wild-type WNK4 inhibits the thiazide-sensitive sodium chloride cotransporter (NCCT)^3,4 and the renal outer medullary potassium ion channel (ROMK),⁵ but increases paracellular chloride permeability.⁶ Some WNK4 mutations identified in PHAII behave as a loss of function for the NCCT inhibition^3,4,7 but as a gain of function for the inhibition of ROMK,^5,7 and further stimulate paracellular chloride transport.^6,8 These effects of WNK4 mutations fit well with the proposed mechanisms for the development of hypertension and electrolyte abnormalities in PHAII. Furthermore, in vitro, WNK1 counteracts the inhibition of NCCT by WNK4⁴ and activates the serum- and glucocorticoid-inducible protein kinase (SGK1), which in turn stimulates the epithelial sodium channel (ENaC).⁹ The observation that heterozygous WNK1-deficient mice had lower blood pressure than wild-type control animals further supports the role of WNK1 in blood pressure regulation.¹⁰ The evidence from studies in patients with PHAII,¹ cell models,^3–9 and genetically engineered animals¹⁰ makes WNK1 and WNK4 strong candidates possibly involved in the . . . [Full Text of this Article]