image: An image of a mouse kidney glomerulus taken on a fluorescence microscope showing cell nuclei in blue, the PIEZO2 gene in magenta, and the renin gene in green. Each dot represents a single mRNA transcript or a small cluster of transcripts.
Credit: Scripps Research
LA JOLLA, CA—The kidneys play a central role in keeping the body’s internal environment stable. By filtering blood, removing waste and carefully controlling fluid and sodium levels, they help maintain healthy blood pressure while ensuring that organs receive the blood they need to function. To carry out this balancing act, the kidneys rely on hormones that respond to constant changes in the body, such as shifts in hydration and sodium intake. One of the most important of these hormones is renin. But how kidney cells sense fluctuations in physical forces—like blood flow and pressure—and translate those cues into precise control of renin release has remained unclear.
Now, scientists at Scripps Research and collaborating institutes have identified a mechanism within the kidneys that allows renin to adjust in real time. Published in Cell on December 4, 2025, the team’s study shows that a protein called PIEZO2 enables kidney cells to gauge physical forces and alter renin output accordingly. The results add fundamental knowledge about how the kidneys maintain stability and what may go wrong in conditions marked by abnormal blood pressure or kidney performance.
“Our findings emerged from a nearly six-year effort, and they explain the process by which the kidneys take a physical force and turn it into a cellular response,” says co-corresponding author Professor Ardem Patapoutian, a Howard Hughes Medical Institute (HHMI) Investigator and the Presidential Endowed Chair in Neurobiology at Scripps Research. “It’s important for understanding how renin is regulated and what can happen when that control falters.”
Patapoutian shared the 2021 Nobel Prize in Physiology or Medicine for discovering the cellular sensors that perceive touch and pressure. These sensors are ion channels—protein gateways embedded in the cell membrane that open in response to physical force. The channel proteins PIEZO1 and PIEZO2 allow charged particles called ions to enter the cell, triggering signals that help coordinate vital functions throughout the body. For example, Patapoutian and a team of researchers recently demonstrated that PIEZO channels contribute to regulating uterine contractions during childbirth by sensing pressure and stretch.
Building on that foundation, this current study evaluated whether similar force-sensing mechanisms also regulate renin in the kidneys. The investigation accelerated when co-corresponding and first author Assistant Professor Rose Hill, a former HHMI Helen Hay Postdoctoral Fellow in Patapoutian's laboratory, noticed an unexpected pattern while studying PIEZO channels in mouse kidney tissue.
“I began the project through a bit of serendipity,” recalls Hill, who now leads a research group at Oregon Health & Science University.
Initially, Hill had been examining PIEZO1 in the kidneys because it appears in many non-nerve tissues, including kidney cells. By contrast, PIEZO2 is usually linked to sensory nerve cells that detect light touch and body position—so Hill wasn’t expecting it to play a major role in kidney function.
“I didn't think PIEZO2 would be involved, but it wound up having this beautiful expression pattern in the juxtaglomerular granular cells—the cell type responsible for producing renin,” she elaborates.
Juxtaglomerular granular cells line the blood vessels that deliver blood into the kidneys’ filters—called the glomeruli—where waste and excess fluid are removed from the bloodstream. These cells adjust renin levels based on chemical cues like sodium concentration, and past research suggested they may also respond to fluctuations in blood flow and pressure. However, scientists didn’t know which protein was responsible for sensing those fluctuations.
This new study found that juxtaglomerular granular cells use PIEZO2 to detect such changes, producing calcium signals that act as internal messengers within the cells. Calcium signaling is a common way cells translate incoming cues into action, enabling activation or suppression of specific responses. In this case, the signals helped fine-tune renin release—a process the team observed directly via live imaging of the kidneys.
To test whether PIEZO2 is required for normal kidney function, the team genetically removed the protein from renin-expressing cells in mice. Under typical conditions, these cells generated rhythmic calcium signals that pulsed in sync with the natural contraction and relaxation of blood vessels. When PIEZO2 was removed, the signals almost completely disappeared.
Because calcium signaling halts renin release, losing it meant the cells no longer received feedback to dial down renin. As a result, renin levels remained abnormally high—even in circumstances where they would otherwise fall—and the hormonal system struggled to adjust to changes in hydration and sodium intake.
Yet one of the most unexpected findings was how removing PIEZO2 affected kidney filtration. The team observed glomerular hyperfiltration—when glomeruli filter blood too quickly—similar to what’s seen early in certain kidney disorders. But further analysis showed no evidence of underlying illness.
The hyperfiltration was largely driven by excess production of angiotensin-(1-7), a hormone that relaxes and widens blood vessels. When those vessels relax, more blood rushes into the glomeruli at once, causing filtration to speed up. When the researchers blocked the signal that causes vessel relaxation, filtration returned to normal.
Although the results are preclinical, they lay groundwork for future studies of human kidney physiology and disease. This insight could inform research on conditions marked by early glomerular hyperfiltration, such as diabetic kidney changes or kidney strain from severe heat exposure. Hill’s current lab is also exploring sensory nerve detection of pressure, inflammation and other signals to better understand how that information modulates kidney function.
According to Patapoutian, the team’s effort opens new paths for studying physical forces as regulators of hormone signaling—in the kidneys and beyond.
“We’ve known the kidneys respond to these forces, but seeing how PIEZO2 helps direct a hormone as central as renin gives us a clearer molecular handle on the process,” he notes. “Notably, this sheds light on a hormonal circuit that the body relies on to maintain balance.”
In addition to Patapoutian and Hill, authors of the study “Renal PIEZO2 is an essential regulator of renin,” include Sebastian Burquez, Jeanine Ahmed and Adrienne E. Dubin of Scripps Research; Jonathan W. Nelson, Georgina Gyarmati, Arjun Lakshmanan and Janos Peti-Peterdi of the University of Southern California; Silvia Medrano, R. Ariel Gomez and Maria Luisa S. Sequeira-Lopez of the University of Virginia; Sepenta Shirvan of UC San Diego Health; James A. McCormick of Oregon Health & Science University; Diana G. Eng and Stuart J. Shankland of the University of Washington; Jan Wysocki, M. Rocio Servin-Vences and Daniel Batlle of Northwestern University; and Jeffrey H. Miner of Washington University in St. Louis.
This work was supported by the National Institutes of Health (grants K99NS133478, K01DK121737, 5R01DK097598, R01HL148044, R01DK132066, R01DK128660, R01DK141178, R01DK064324 and S10OD021833), the American Heart Association (grant AHA 20CDA35320169), the American Society of Nephrology, the Collins Medical Trust and the Howard Hughes Medical Institute.
About Scripps Research
Scripps Research is an independent, nonprofit biomedical research institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr-Skaggs, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.
Journal
Cell