Study could help researchers design more effective drugs
Researchers at Oregon Health & Science University have determined how a genetic defect increases salt (sodium chloride) absorption in the kidney, causing high blood pressure. These results could guide future development of more effective drugs for this deadly disease. The study will be published in the April 1 issue of The Journal of Clinical Investigation.
More than 40 million people suffer from hypertension, causing more than 23,000 deaths each year. By studying a rare form of hypertension called pseudohypoaldosteronism type II (PHAII), which is caused by a simple genetic defect, OHSU researchers were able to determine how a new family of kinases affects blood pressure.
"We believe understanding the causes of these simpler forms of hypertension will help us understand the cause of more common types. We may find that the same genes with slightly different mutations cause various forms of the disease," said David Ellison, professor of medicine (nephrology and hypertension)and physiology and pharmacology in the OHSU School of Medicine, and physician at Portland Veterans Affairs Medical Center.
By looking at the proteins that cause PHAII, WNK kinases, the researchers were able to determine how the body retains excess salt, resulting in high blood pressure. They found that one of these proteins, called WNK4, removes NCC, the protein that transports salt out of the cell membrane, regulating blood pressure in the process. When WNK4 is mutated and doesn't work, more salt is retained by the body. Salt retention is also responsible for other hypertensive syndromes routinely evaluated by Ellison and his colleagues Susan Bagby, M.D., professor of medicine (nephrology and hypertension) and Veronica Legg, M.S., F.N.P., instructor of medicine (nephrology and hypertension)at the OHSU Hypertension Clinic.
NCC is the protein target of high blood pressure treatments known as diuretics, which help remove excess salt from the body, lowering blood pressure. Diuretics were recently reaffirmed as one of the most effective treatments for high blood pressure. But diuretics can increase the risk for diabetes and low blood potassium. Researchers hope what they've learned about the connection between WNK4 and NCC, as well as how these two work together to lower blood pressure, will help them design drugs that are as effective as diuretics with fewer side effects.
"The important thing about the study is that this is a completely novel class of proteins (WNK kinases) that was just discovered two years ago. No one had any idea of what this class did. Now it looks like this class of kinase is really important for regulating salt transport all over the body," said Ellison.
Because salt transport impacts many diseases besides high blood pressure, such as cystic fibrosis, Ellison said WNK kinases could influence many diseases.
The next steps are to look at the specifics of how the interaction between WNK4 and NCC occurs and at how other transport systems are impacted by this interaction. A second type of WNK kinase, WNK1, is found in body tissues that have chloride transport such as the pancreas and gut. Further research may show that WNK1 is the master kinase controller, thus targeting it with a drug could have a domino effect that could help patients with cystic fibrosis, hypertension and many other diseases impacted by salt and chloride absorption.
Ellison worked on this study with Chao-Ling Yang, M.D., research instructor in medicine (nephrology and hypertension) in the OHSU School of Medicine.