The study will appear in an upcoming issue of the Proceedings of the National Academy of Sciences.
"This is a classic example of how basic research could lead to better understanding of human diseases and potentially to new therapeutic methods," said Dr. Bing-E Xu, assistant professor of pharmacology at UT Southwestern and lead author of the study.
The enzyme WNK1 is known to cause a form of hypertension, abbreviated PHA II, but until now the method by which it affected blood pressure was unclear. By studying animal and human cells in culture, UT Southwestern researchers determined that WNK1 interacts with and activates another enzyme, SGK1, which is well known to lead to the activation of sodium ion channels in kidney cells.
"The kidney plays a very important role in controlling blood pressure by controlling how much sodium gets reabsorbed back into the kidney and the blood," said Dr. Chou-Long Huang, associate professor of internal medicine at UT Southwestern and co-senior author of the study. "Sodium comes into the kidney cell through these channels and is then returned to blood circulation through another sodium transporter," he said. "The sodium channel critically governs how much sodium gets reabsorbed."
Normally, the kidney filters and reabsorbs about 99 percent of sodium from the blood and returns it to the body, excreting 1 percent through urine, said Dr. Huang, a nephrologist.
However, if salt ingestion remains the same and the kidneys reabsorb 99.9 percent of salt, too much salt returns to the blood, increasing blood volume and leading to hypertension. If less than 99 percent is absorbed, low blood pressure develops.
Dr. Huang said that not everyone who eats too much salt ends up with hypertension, but some population groups, such as African-Americans, are more prone to develop salt-sensitive high blood pressure, suggesting that genetic factors may play a role in the disease.
One extension of the current work may lead to a better understanding of hypertension that is induced by low potassium intake. Previous studies have shown that diuretics, a class of drugs commonly used to control hypertension, also cause potassium wasting, or low potassium levels, in patients.
"Studies have shown that if you are taking diuretics and let your potassium level fall, the diuretics are not as effective," Dr. Huang said. "But if you take diuretics and you supplement with potassium, you can lower blood pressure more effectively." Dr. Huang and his research group currently are conducting studies to determine whether low potassium intake increases WNK1 activity, leading to hypertension.
The WNK1 enzyme was first identified and cloned in 2000 by UT Southwestern researchers led by Dr. Melanie Cobb, co-senior author on the PNAS paper and dean of UT Southwestern Graduate School of Biomedical Sciences. After cloning the enzyme, Dr. Cobb's research group examined what proteins might be regulated by WNK1, and found that SGK1 was one of those proteins. Because he works on ion channels, including sodium channels, Dr. Huang joined efforts with Dr. Cobb to study how WNK1 regulates sodium channels.
"We have been working on WNK1 for several years now and these findings are unexpected from initial studies," said Dr. Cobb. "What is particularly satisfying and exciting is the ease with which we could establish such a collaboration at UT Southwestern to study the physiological and medical implications of our findings."
Other UT Southwestern researchers involved in the study were Steve Stippec, pharmacology research associate; Dr. Ahmed Lazrak, instructor of internal medicine; Dr. Xin-Ji Li, research associate in internal medicine; Dr. Byung-Hoon Lee, postdoctoral researcher in pharmacology; and Dr. Bernardo Ortega, postdoctoral researcher in internal medicine. Former postdoctoral researchers Dr. Po-Yin Chu and Dr. Jessie M. English also contributed.
The research was supported by the National Institutes of Health and the Welch Foundation.
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Journal
Proceedings of the National Academy of Sciences