Inflammatory Genes Linked To Salt-sensitive Hypertension

It may sound odd but mounting evidence suggests that inflammation, a part of the immune response implicated in diseases such as cancer, Alzheimer’s and diabetes, may also help translate stress into high blood pressure.

“There is a concept that hypertension is an inflammatory condition,” says Dr. Haidong Zhu, molecular geneticist at the Medical College of Georgia. She’s among the scientists who believe the connection between stress, inflammation and hypertension is the kidneys’ ability to release sodium.

When stress activates the sympathetic nervous system (the fight-or-flight mechanism), the body increases production of interleukin 6, a pro-inflammatory factor, which ultimately leads to production of other inflammatory factors such as C reactive protein.

Stress also prompts the body to hold onto sodium to help temporarily raise blood pressure so you can deal with the situation, says Dr. Gregory Harshfield, director of MCG’s Georgia Prevention Institute and an expert on what happens when the body doesn’t let go afterward. It’s called impaired stress-induced pressure natriuresis, which Dr. Harshfield has documented in young, healthy teens.

Dr. Zhu is now leading research to see if the reactions are related – if sodium handling goes awry under stress because the teens have mutations in four sets of stress-activated inflammatory genes: interleukin 6, interleukin 6 receptor, cytokine signal transducer and C-reactive protein.

“Our long-term goal is to be able to identify a subgroup of individuals with a certain genetic profile that has an increased risk of developing high blood pressure in a stressful environment,” says Dr. Zhu, who recently received a two-year, $300,000 grant from the National Heart, Lung and Blood Institute

If she’s right, these individuals could likely benefit from targeted therapy that might include a low-salt diet, physical activity and maybe anti-inflammatory drugs, says Dr. Zhu.  Nearly one in three Americans is hypertensive and more than half have salt-sensitive hypertension, she notes.

“Cardiovascular diseases, including hypertension, are complex diseases with a lot of gene-environment interaction, and stress is now a part of people’s daily lives,” she says. 

“We have found hypertension associated with inflammation and we have found stress associated with hypertension. There is evidence suggesting that in salt-sensitive  hypertension there are increased levels of inflammation factors such as interleukin 6 and C-reactive protein,” Dr. Zhu says. “Even high-normal blood pressure is associated with a pro-inflammatory condition.”

Additionally, animal studies have shown salt-sensitive hypertension induced by the powerful blood-vessel constrictor angiotensin 2 can be prevented by drugs that suppress the immune response and consequent inflammation.

“There are many pieces of evidence and we are trying to link them together,” says Dr. Zhu.

Her research team is looking at genetic variations of four inflammatory genes in 500 15- to19-year-olds with normal blood pressure.  The teens, already enrolled in studies at MCG’s Georgia Prevention Institute measuring the effects of stress on the cardiovascular system, were put on a diet for four days to regulate sodium intake, then came to the GPI where they rested for an hour, played a three-dimensional, racing video game for an hour, then rested for an hour. Blood and urine samples were taken throughout the period. For this study, researchers will also collect DNA material from the  mouths of as many parents as possible to confirm their findings in the children.

Pilot data indicate that black teens with normal blood pressure and a certain variation of the interleukin 6 gene have significantly reduced sodium excretion in the urine following stress. Researchers have further implicated the inflammatory factor’s role in blood pressure regulation by showing that following stress, circulating levels of interleukin 6 rise and are still up an hour after the stressor is gone.

Dr. Zhu suspects that even without the genetic variations, inflammation affects blood pressure under stress, so she’ll be looking at its impact alone and in concert with the mutations.

“We believe this research will provide novel insight into the interactions between stress, inflammation and genetics and their contribution to the pathogenesis of essential hypertension,” she says.

The relationship between inflammation and high blood pressure, including how cytokines affect blood pressure elevation, also is the subject of a five-year, $11 million National Heart, Lung and Blood Institute Program Project grant underway at MCG under the leadership of Dr. R. Clinton Webb, chair of the Department of Physiology.