A new study has identified a critical "pressure sensor" inside the kidney that helps the body control blood pressure and fluid levels. The finding helps explain how the kidneys sense changes in blood volume — something scientists for decades have known occurs but didn't have a mechanistic explanation.
Researchers at Oregon Health & Science University and collaborating institutions discovered that a protein called PIEZO2 acts as a mechanical sensor in the kidney. When blood volume changes, this protein helps trigger the release of renin, a hormone that starts a chain reaction known as the renin-angiotensin-aldosterone system, or RAAS. The system is one of the body's main tools for keeping blood pressure stable and making sure the body has the right balance of salt and water.
The study, published today in Cell, shows that without PIEZO2, the kidney releases too much renin. This throws the RAAS off balance and causes the kidneys to filter blood too quickly, something that can lead to health problems if it continues over time.
"We've known for decades that mechanical forces in the kidney help control renin, but we didn't know what molecules were actually sensing those forces," said lead and co-corresponding author Rose Hill, Ph.D., assistant professor of chemical physiology and biochemistry in the OHSU School of Medicine and the Vollum Institute at OHSU. "Finding PIEZO2 in these specific kidney cells was a surprise, because this ion channel was thought to be mainly a touch sensor in the nervous system."
The findings highlight a major gap in our understanding of how kidneys regulate blood pressure, Hill said.
Much of Hill's research was conducted as a postdoctoral researcher working with Scripps Research scientist Ardem Patapoutian, Ph.D., who won the 2021 Nobel Prize for discovering ion channels — like PIEZO2 — that help the body sense pressure, touch and temperature. Patapoutian is co-corresponding author for the study.
Hill, whose lab studies sensory pathways inside the kidneys, said the discovery grew from an unexpected observation.
"When we first saw PIEZO2 in these cells, it immediately caught our attention," she said. "It helped us connect the dots. This protein can detect mechanical forces, and these same forces are known to affect renin levels. It turned out PIEZO2 is the missing link."
The researchers found that PIEZO2 helps the kidney adjust to both short- and long-term changes in blood volume, such as dehydration or increased fluid intake. Without PIEZO2, the kidney behaves as though the body is constantly low on blood volume, even when it isn't.
"PIEZO proteins act as pressure sensors in the nerves in the cardiovascular system," Hill said. "Now we see that PIEZO2 also works as a pressure sensor inside the kidney. It shows these proteins are important for sensing blood pressure throughout the body, not just in nerves."
While the discovery does not yet lead directly to new treatments, Hill said it opens important new research directions.
"We don't have good drugs that target these pressure-sensing channels yet," she said. "But understanding this system could eventually help us with diseases where the kidneys are repeatedly stressed by dehydration or low blood volume."
One example is chronic kidney disease of unknown origin, known as CKDu, which affects many young agricultural workers in very hot climates.
"These workers become dehydrated, and we don't fully understand how that leads to early kidney failure," she said. "If volume loss affects PIEZO2 or the cells that make renin, this pathway could be part of the answer."
In addition to Hill, other OHSU co-authors include James McCormick, Ph.D., renal research director in the OHSU School of Medicine. A full list of authors is available online.
This study was supported by the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health, under Award number K99NS133478, National Institute of Diabetes and Digestive and Kidney Diseases, of the National Institutes of Health, under Award numbers K01DK121737, 5R01DK097598, R01DK132066, R01DK128660, R01DK141178, R01DK064324, and National Heart Lung and Blood Institute under Award number R01HL148044, American Heart Association Award number 20CDA35320169, The Collins Medical Trust, ASN Kidney Cure, and a Howard Hughes Medical Institute Investigator Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders.
