Pass the Salt?

Richard Wainford studies the connection between salt and high blood pressure. Photo by Michael D. Spencer

Let’s face it: salt is delicious. Sprinkle it on tomatoes and they pop with flavor; shake it over popcorn and it’s movie time. Even Nelson Mandela noted its worth in his inaugural address: “Let there be work, bread, water, and salt for all,” he said.

But when it comes to diet and high blood pressure, salt has long been one of the bad guys, right up there with (and related to) bacon and bologna. Too much sodium can make your body retain water, increasing pressure within blood vessels and leading to hypertension. And runaway blood pressure can lead to a host of maladies, from kidney damage and vision loss to stroke and heart disease. Hypertension is directly responsible for almost 13 percent of all global deaths, according to the World Health Organization, and the American Heart Association urges us to take an online pledge to trim salt from our diets. Their slogan: “I love you salt, but you’re breaking my heart.”

Most Americans do eat too much salt—3.5 grams of salt each day, more than 7 times what we need, according to the Centers for Disease Control. But the extra salt doesn’t affect everyone equally. According to Richard Wainford, assistant professor of pharmacology and medicine in the Boston University School of Medicine (MED) department of pharmacology and experimental therapeutics, only an estimated half of adults are salt-sensitive: if they eat too much salt, their blood pressure goes up. For the other half, salt has little or no effect on blood pressure. But nobody knows exactly why, and there’s no easy way to tell who’s who.

“Something has got to be working in your body to get rid of that salt,” says Wainford, who heads a laboratory at the Whitaker Cardiovascular Institute. “We don’t know what that is. So if we don’t know what’s working in a healthy patient, how can we expect to fix something when it’s broken? That’s where I come in.”

Wainford specializes in the complex science of homeostasis—how the body maintains a stable balance of substances like sodium, glucose, and iron throughout its tissues and how this impacts blood pressure regulation. His research, funded by two grants from the National Institutes of Health’s National Heart, Lung, and Blood Institute, has already led to several insights about how our bodies regulate salt. His ultimate goal is to develop biomarkers for salt-sensitivity, which could lead to better diagnostics and treatment for high blood pressure.

“Something has got to be working in your body to get rid of that salt. We don’t know what that is.” – Richard Wainford

“We do see salt as a contributor to high blood pressure, but it also does a lot of other things,” says Haralambos Gavras, a MED professor of medicine and an expert on hypertension. “It’s important to find out the mechanisms—that way, we can be more decisive in the treatments.”

One of the key organs for human homeostasis is the kidney, which helps regulate water, salt, and iron in the blood by choosing to excrete certain substances in the urine. Another key organ is the brain, which helps control the kidneys. Wainford studies the kidney-brain conversation by examining a particular signaling pathway, one that sends messages through certain molecules, known as gαi_2-proteins, in the brain. When a person eats or drinks salt, signals along this pathway tell the brain to slow down communication from the brain to the kidney, and also for the kidney to increase the amount of salt in urine. The kidneys, left to their own devices and receiving constant communication from the brain, excrete less sodium in the urine. It’s a complicated chain of events, and Wainford wants to know exactly how this convoluted system comes together. So he studies how it works in rats. “In a simple sense, we study how rats pee,” says Wainford. “It’s a simple way to gain insight into the conversation between the brain and kidney.”

In one of his first experiments, Wainford worked with several breeds of salt-resistant rats, animals that can eat as much salt as they want with no effect on blood pressure. (Some rats are born that way, some bred.) “They maintain sodium balance—what goes in comes out. So they’re doing fine. But how is that happening?” asks Wainford. “We wanted to know if this protein pathway—the gαi₂ pathway—is involved. So we did the most simple experiment ever. I took these little rats that don’t get high blood pressure. We fed them salty diets for three weeks, and then we took their brains and looked at the expression of these proteins.”

“In a simple sense, we study how rats pee,” says Wainford. “It’s a simple way to gain insight into the conversation between the brain and kidney.”

He found a dramatic increase of this protein pathway in a brain region known as a “hot spot” for cardiovascular regulation. “It sends communications directly to the kidney and it sends communications directly to other brain centers,” says Wainford. “And we were like, ‘Wow. That’s kind of interesting.’ So then we took it away.” In the same rats, Wainford blocked the signal pathway by infusing the rats with a specific sequence of DNA that prevented them from making the gαi_2-protein. Then he gave the animals salty food again, but this time, they couldn’t get rid of the extra salt. As a result, they got high blood pressure.

“When healthy people eat salt, the activity of their central nervous system is turned down to get rid of it,” says Wainford. “When you remove this protein pathway in the brain of salt-resistant rats, that doesn’t happen. They’re not able to turn down the activity of the brain to that same extent.” Wainford, who published this research in Hypertension in 2013, believes this signaling pathway is one of several that affect the control of blood pressure. Other studies in humans have shown that a tiny defect in the gene for this protein—one single base pair off—is linked to hypertension. But Wainford’s group is the first to find how it works: a clear molecular mechanism that regulates the communication between the brain and the kidney.

“It’s an interesting piece of work,” says Gavras, who cautions that this is still basic research and much more remains to be done. “It’s promising, but let’s see where it goes in the long run.”

Wainford followed this study with similar tests on salt-sensitive rats, and with a more drastic measure of removing the animal’s renal nerves entirely, severing all communication between the brain and kidneys. Surprisingly, this kept the rats’ blood pressure low and seemed to have no other ill effects. (The SYMPLICITY trials on humans have tried the same tactic of removing renal nerves from treatment-resistant hypertensive patients, with mixed results.)

“Clearly the impact of the renal nerves on blood pressure regulation in human subjects is complicated. I think the removal of the renal nerves is a very powerful technique; it just needs to be done right, and studied right, and in the right population,” says Wainford. “Ultimately, our goal is to more fully understand the mechanisms of how the brain and the kidney interact to regulate blood pressure. The more we understand that, the better we can treat patients.”