Protein Mutation Is Linked to Hypertension in Some Pregnancies
Researchers have uncovered a rare protein mutation that makes some women more likely to suffer pregnancy-induced hypertension, a debilitating condition that affects as many as 240,000 childbearing women in the United States each year.
A single mutation in a protein called the mineralocorticoid receptor causes high blood pressure that begins early in life and that is severely exacerbated during pregnancy, a team from the Yale School of Medicine reports in today’s Science.
Long believed to be involved in blood pressure regulation, mineralocorticoid is a steroid hormone found in kidney cells that regulates salt uptake.
Discovery of the mutation in the receptor may shed light on the long-elusive cause of high blood pressure during pregnancy, a potentially life-threatening condition that affects 6% of pregnancies.
The mutation also increases the risk of pre-eclampsia, a pregnancy-related disorder characterized by fluid retention, elevated blood pressure and protein in the urine.
“For the first time, we have identified a [molecular] mechanism for the development of high blood pressure in pregnancy,” said Dr. Richard P. Lifton of the Howard Hughes Medical Institute at Yale, the senior author of the study.
Road Map for Research
The discovery could lead to new drugs to treat pregnancy-induced hypertension and tests to identify women who are at high risk for pre-eclampsia. It also could lead to new treatments for a variety of other diseases that involve malfunctions in steroid receptors.
“This is a very fascinating discovery of what looks like an extremely rare and unusual form of hypertension,” said Dr. Marshall Lindheimer of the University of Chicago.
Although the findings do not explain the overall causes of hypertension, he said, they could provide a road map for further research.
“[Scientists] always start out with wild rare things. Then we find out that an almost similar mechanism is involved in [a much more common disorder]. This may be the first step in understanding salt-sensitive hypertension,” said Lindheimer.
The original mutation was found in a 15-year-old boy who was part of a study looking for the causes of early onset hypertension.
Further investigation revealed that all 11 members of the boy’s family who had inherited the mutation developed hypertension before age 20, said Yale nephrologist David Geller, who discovered the mutated gene.
Cell cultures of normal and mutant receptors showed that the mutant receptor was permanently “switched on,” or activated, although its normal trigger, a hormone called aldosterone, was absent. The activation was triggered by progesterone, which normally turns off the receptor. The impact on mutant receptors is particularly acute for childbearing women because progesterone levels rise sharply during pregnancy.
Lifton and his colleagues examined the clinical histories of the two women in the family who had become pregnant. Severe hypertension forced both women to undergo pre-term delivery in all five of their pregnancies. Neither of the women developed pre-eclampsia, however.
In these women, overstimulation of the receptor caused them to absorb excessive amounts of salt and water, resulting in dangerously high blood pressure.
“Now that [Lifton and colleagues] have proved this molecular link between this receptor and severe hypertension, the obvious next thing is to look at other factors that can regulate the receptor. From that point of view, the finding is exciting,” said cell biologist Susan Fisher of UC San Francisco.
In fact, the study found that progesterone derivatives, naturally present in both men and women, also activate the faulty receptor. Researchers think that some of these hormones may contribute to the development of hypertension in men who carry the same mutation, said Lifton.
Lifton said that the mutation is rare in the general population and therefore a rare cause of pregnancy-related hypertension.
In the past, the study of rare disorders has led to key insights into more common disorders. For example, the identification of the mutated receptor causing severe elevation in cholesterol, a disease that affects one in a million people, eventually led to the development of cholesterol-lowering drugs widely used today, he said.
In fact, the mineralocorticoid mutation has important implications for the drug treatment of other common diseases.
“We think we’ve uncovered a general property of how steroid receptors work, which will help us design new drugs to turn receptors on and off,” Geller said.
Such drugs could be used to treat breast and prostate cancer, diabetes and thyroid disease.
Early Intervention May Be Possible
Lifton’s team is already developing a genetically altered mouse that possesses a mutation in the mineralocorticoid receptor gene, a complex process that could take more than a year.
“This would give us the opportunity to try a range of treatments before moving to humans,” Lifton said.
Clinical studies could help determine if progesterone promotes increased salt reabsorption in other forms of hypertension in pregnant women.
“We may be able to select a subset of [pregnant female] patients in whom salt restriction or treatment with specific anti-hypertensive drugs may be helpful,” Lifton said.
Lifton hopes that this study will spur further investigation. Does progesterone act the same way in other forms of pregnancy-related hypertension? Do other normal hormones of pregnancy have abnormal effects that promote high blood pressure?
“One of the things that makes hypertension difficult to study is that it is multi-factorial. There are many ways to get to the same end point,” said Fisher, who now is researching the role of the placenta in pre-eclampsia.
“Ultimately one would like to have preclinical tests to identify women of particular risk before hypertension or pre-eclampsia develop,” Lifton said. “If we had those tests, we would be able to intervene with change in diet, lifestyle or medication before morbid clinical outcomes could develop.”
