Thomas Kleyman, MD, professor of medicine and chief of the renal-electrolyte division at the University of Pittsburgh Medical Center, is a senior author of the study.

Sodium channels found outside the kidney do some heavy lifting to maintain functional kidneys and normal blood pressure, a study published recently in the journal Hypertension reported. The extra-renal sodium channels discovered by geneticists and nephrologists at the University of Pittsburgh are a promising new target for medications that could potentially lower blood pressure without raising blood potassium levels.

Thomas Kleyman, MD, professor of medicine and chief of the renal-electrolyte division at the University of Pittsburgh Medical Center (UPMC) and Ryan Minster, PhD, assistant professor of human genetics at Pitt’s School of Public Health, are the senior authors of the study.

Kleyman said, “This study may help us someday identify people with specific, subtle genetic mutations that predispose them to a type of hypertension acting outside the kidneys. Knowing that, we can better help that person control their blood pressure.”

According to the U.S. Centers for Disease Control and Prevention, high blood pressure is the country’s biggest public health problem, with nearly half of all adults suffering from high blood pressure and only one in four individuals adequately medicated to keep their blood pressure within the normal range. Moreover, high blood pressure is associated with higher risks of kidney disease and stroke, and disproportionately affects the African American population.

Ryan Minster, PhD, assistant professor of human genetics at Pitt’s School of Public Health, is a senior author of the study.

Misregulation of fluid and electrolyte levels in the circulation is the primary cause of high blood pressure, which in turn stresses the walls of blood vessels and damages organs. Epithelial sodium ion channels (ENaCs) embedded in the membranes of cells provide finely regulated passageways that control the volume of fluid in the circulation, by adjusting the flux of sodium into and out of cells.

The genes SCNN1A, SCNN1B, and SCNN1G encode the alpha, beta, and gamma subunits of ENaC, respectively. Mutations in these genes disrupt the regulation of blood pressure significantly. Interestingly, associations between mutations in the gene SCNN1D that encodes the delta subunit of ENaC have not been reported. A few genetic variations in ENaC encoding genes have been linked to changes in sodium transport and blood pressure regulation, but the effect of most ENaC sequence variations remain a mystery.

“We knew of ENaC variants with large effects on blood pressure, but I wanted to determine if there are other ENaC variants that exert a more moderate effect on blood pressure,” said lead author of the study, Brandon Blobner, PhD. “Working with Dr. Ryan Minster, I was able to access about 28,000 whole genome sequences linked with medical histories of blood pressure, kidney function, and stroke to organize and harmonize the data. From there we were able to pull out findings on hypertension and their link to mutations in the sodium channel.”

Brandon Blobner, PhD, is the lead author of the study.

Blobner sourced and analyzed data from individuals recruited to fourteen studies in the TOPMed (Trans-Omics in Precision Medicine) whole-genome sequencing (WGS) program or the Samoan Good Health study, funded by the National Heart, Lung and Blood Institute (NHLBI). Based on the WGS data, the researchers explored the association of low frequency and rare variants in ENaC subunit genes, with systolic, diastolic, mean arterial, and pulse pressure.

“We made use of previously established research protocols, mainly the sequence kernel association test (SKAT),” said Blobner.  “We determined that SKAT would be the most appropriate clustering test to use in this study because SKAT is agnostic to the direction and magnitude of effect of the variants included in the test and we had no prior knowledge of how individual variants might alter ENaC function.”

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

The investigators found that changes in ENaC’s delta subunit affect blood pressure. This subunit of the sodium channels is expressed outside the kidney—in immune cells, and in epithelial cells that line the lungs, heart, and colon.

The team also found that variants in the SCNN1A and SCNN1B genes were associated with diastolic and mean arterial pressure, while variants in SCNN1D were associated with systolic, diastolic, mean arterial, and pulse pressure. Variants SCNN1B and SCNN1D were also associated with the rate of filtration in the glomeruli of the kidney, but these were not associated with stroke.

Blobner said, “Our findings were unexpected. There had been some hints that mutations to salt-processing channels outside the kidneys affected blood pressure, but it would have been impossible to confirm the mechanism without the massive genetics databases that we had access to through cross-disciplinary partnerships.”

“I’m a nephrologist. My entire career has been dedicated to understanding the kidney and its role in maintaining sodium levels to moderate blood pressure,” said Kleyman. “But our research in the last several years has expanded my focus. This study cements that we must branch beyond the kidney to better target blood pressure medications.”

Some blood pressure medications can increase blood potassium levels (hyperkalemia) which can be fatal. Hyperkalemia is also a sign of kidney malfunction. If high blood pressure can be regulated by targeting sodium channels outside the kidney, such medications would potentially have a lower risk of hyperkalemia than the current standard of care.

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