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The kidneys are often the unsung heroes in maintaining healthy blood pressure, filtering 180 liters of fluid and a pound of salt each day to keep levels in check. But new research by geneticists and nephrologists at the University of Pittsburgh shows that, surprisingly, a cellular channel outside the kidney does some of the heavy lifting when it comes to keeping blood pressure under control.

The discovery was published today in the Journal of the American Heart Association Hypertensionpoints to a promising new target for clinical trials to test existing medications for reduction blood pressure.

“Our findings were completely unexpected,” said Brandon Michael Blobner, Ph.D., who conducted the research as part of his PhD at Pitt and is now a bioinformatics scientist at BlueSphere Bio in Pittsburgh. “There had previously been some hints that mutations in extrarenal salt recycling channels affected blood pressure, but it would have been impossible to confirm this mechanism without the massive genetic databases we had access to through an interdisciplinary partnership.”

Almost half of US adults have high blood pressure or hypertension related to chronic kidney diseases and stroke, and it disproportionately affects black people. Only 1 in 4 people have high blood pressure under control, making it one of the nation’s biggest public health problems, according to the US Centers for Disease Control and Prevention.

High blood pressure is caused, in particular, by fluid and salt levels that fail, putting strain on artery walls and damaging blood vessels and organs.

Pitt’s research focused on the passageways, or channels, that the membranes of some cells use to regulate fluid volume based on the amount of sodium in the cells. Blobner was interested in whether mutations in the genes encoding the subunit of this channel could affect blood pressure.

With the support of Thomas Kleiman, MD, the Sheldon Adler Professor of Medicine at Pitt, Blobner worked with Ryan Minster, PhD, assistant professor of human genetics in the Pitt School of Public Health, to create a dataset of genomic sequences and blood pressure recordings from more than 28 000 people who participated in either the Trans-Omics in Precision Medicine (TOPMed) Whole Genome Sequencing Project or the Somoan Soifua Manuia study.

“One of the really exciting things about this project for me was that it was so focused and hypothesis-driven,” Minster said. “Often with these big genome projects, we’re more agnostic—casting a wide net—and it can take decades to confirm a discovery. This project made a significant discovery extremely quickly.”

Scientists know that rare mutations in the genes encoding the channel’s alpha, beta, and gamma subunits—all three found in a kidney cells – can cause dangerous spikes in blood pressure. But when scientists looked at more subtle mutations, they found that a fourth subunit, delta, affects blood pressure. It is important to note that delta is found outside the kidneys, in immune cells, as well as in lung, heart, and colon cells.

“I’m a nephrologist — my entire career has been devoted to understanding the kidney and its role in maintaining sodium levels to moderate blood pressure,” said Kleiman, who is also chief of the Renal Electrolytes Division at UPMC and senior author of the study. “But our research over the past few years has broadened my focus. This study reinforces that we need to look beyond the kidney to better target blood pressure medications.”

One of the dangers with a little blood pressure medication is that they can cause high potassium levels, which can be fatal. But this problem is related to poor kidney function. Theoretically, if a person has high blood pressure due to fluid and salt imbalances caused by malfunctioning channels in cells outside the kidney, such medications may be an effective treatment with less risk of high potassium levels.

“One of the things we’re particularly interested in at UPMC is therapeutics — you want to give the right drug to the right person at the right time,” Clayman said. “This research may help us one day to identify people with specific, subtle genetic mutations that predispose them to a type of hypertension that acts outside of the kidney. By knowing this, we can better help that person control them blood pressure.”

Remind me again why salt is bad for you?

Additional information:
Rare variants in genes encoding epithelial Na+ channel subunits are associated with blood pressure and kidney function, Hypertension (2022). … TENSIONAHA.121.18513

Citation: Study of rare genetic mutations leads scientists to unexpected blood pressure discovery (2022, October 4) Retrieved October 4, 2022 from .html

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