Published Online
on March 17, 2003

A more recent version of this article appeared on April 1, 2003

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Submitted on December 10, 2002
Revised on December 31, 2002

The Role of Wnk4 in Polygenic Hypertension. A Candidate Gene Analysis on Rat Chromosome 10

Jan Monti; Heike Zimdahl; Herbert Schulz; Ralph Plehm; Detlev Ganten; and Norbert Hübner^*

From Max-Delbrück-Center for Molecular Medicine (J.M., H.Z., H.S., R.P., D.G., N.H.), Berlin-Buch, Germany; Franz-Volhard-Clinic, HELIOS-Klinikum, Charite, Humboldt-University Berlin (J.M.), Germany; and the Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie University Berlin (H.S., D.G., N.H.), Germany.

^* To whom correspondence should be addressed. E-mail: nhuebner{at}mdc-berlin.de.

Abstract--Linkage analyses in experimental crosses of stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar-Kyoto (WKY) rats have strongly suggested the presence of quantitative trait loci (QTL) influencing blood pressure and ACE levels on rat chromosome 10, which have been confirmed in multiple independent studies. Analysis of the orthologous region on human chromosome 17 also revealed significant linkage to blood pressure in several populations. Wnk4, a gene previously identified to cause pseudohypoaldosteronism type II, a rare mendelian form of arterial hypertension, is located on human chromosome 17. The hypothesis has been advanced that molecular variants of this gene might contribute to common polygenic forms of hypertension, since Wnk4 is located in a region of conserved synteny that demonstrates an overlap between quantitative trait loci for primary hypertension in humans and rats. In this report, we describe the confirmation of the blood pressure QTL on rat chromosome 10 by congenic approaches, spanning the Wnk4 locus. Comparative analysis of the complete coding sequence of Wnk4 in SHRSP and WKY strains revealed no mutation and demonstrated high conservation between rat and human proteins. Furthermore, comparison of mRNA levels in the kidney showed no differences between SHRSP and WKY. Additionally, we excluded a secondary effect of blood pressure on the transcriptional regulation of Wnk4. Our results fail to support a material contribution of Wnk4 to blood pressure regulation in this model of polygenic hypertension. Thus, Wnk4 is likely not to represent the underlying disease gene for the QTL captured in chromosome 10 congenic animals.

Key words: blood pressure • genetics • hypertension, genetic • rats, inbred strains • rats, stroke-prone SHR

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