Study Describes Molecules That Control Blood Pressure

(HealthDay News) -- Researchers are reporting a newly discovered molecular mechanism that makes blood pressure go up or down -- knowledge that could lead to new treatments for the hypertension that affects at least 50 million Americans.

A report published Nov. 1 in the Journal of Clinical Investigation is the latest in a series of studies on molecules called WNK kinases, which are proteins that help regulate blood pressure, said study co-author Dr. David H. Ellison, a professor of medicine at the Oregon Health & Science University.

"It has been known that these kinases are important for regulating blood pressure, because mutations of them cause hypertension," Ellison said. "This report adds two things that were not previously known."

One new finding was that one kinase, WNK3, plays a key role in regulating NCC, a protein that normally keeps salt in the body. Salt content helps govern blood pressure; more salt means higher pressure.

Another finding was that WNK3 does not act alone but in conjunction with two other kinases, WNK1 and WNK4. The interaction of WNK3 and WNK4 is important, Ellison said, because it helps explain why fruits and vegetables, which are rich in potassium, help keep blood pressure low.

Start with WNK4. If extra copies of a gene for the normal version of the kinase are put into a laboratory animal, its blood pressure goes down. If extra copies of a mutated version of WNK4, differing in only one of the amino acid units making up the protein, are added, its blood pressure goes up, Ellison said.

"It has been shown that the mutant of WNK4 causes disruption of the normal form of its metabolic pathway," he said. "There is continuing salt resorption caused by an interaction with the normal form, which turns off the normal form."

Potassium keeps blood pressure down by stimulating production of WNK4, Ellison said. The extra WNK4 reduces the activity of WNK3. The entire complex of three WNK kinases also acts as a unit, modifying the activity of the NCC protein.

"What happens is that WNK4 normally inhibits WNK3, reducing salt resorption," Ellison said. "Mutant WNK4 blocks this effect, thereby generating more active WNK3, increasing salt transport and causing hypertension."

The WNK kinases are members of one of the largest protein families in the human body. There are 518 of them, coordinating a wide variety of biological functions. The WNK kinases, which were discovered in 2000, have been objects of research since a group led by Dr. Richard P. Lifton, who heads his own laboratory at Yale University, found a link between them and a rare inherited form of high blood pressure, called familial hyperkalemic hypertension.

Lifton had no immediate comment on the new report.

The new research is still at a basic level, Ellison said. "If we develop a new pharmaceutical approach to hypertension, that could be helpful," he added.

"I think what this report highlights is the importance of understanding the protein level of expression in every kind of cell," said Melanie Cobb, a professor of medical sciences and pharmacology at the University of Texas Southwestern Medical Center at Dallas, where the first WNK kinase was cloned.

"It certainly makes clear that they interact more among themselves than might be expected," Cobb said. "It highlights the complexity of interactions among the proteins, and the importance of understanding those interactions."

More information
A guide to lowering high blood pressure is offered by the U.S. National Heart, Lung, and Blood Institute.