RNA molecular pathway steers stem cells to aid kidney development
Manipulating level of key molecules could boost the number of blood-filtering nephrons and protect against chronic kidney disease, UTSW researchers say
DALLAS – June 24, 2025 – UT Southwestern Medical Center researchers have discovered an RNA pathway that appears to push stem cells to form nephrons, the functional units of kidneys. Their findings, published in Nature Communications, could lead to therapies that increase the number of nephrons in individuals at risk of chronic kidney disease (CKD), the study authors say.
“We showed that the RNA methylation pathway is essential for normal kidney development and can be modulated to increase nephron endowment,” said study leader Vishal Patel, M.D., Professor of Internal Medicine in the Division of Nephrology at UT Southwestern.
On average, a human kidney has about 1 million nephrons, structures that remove waste and excess salt and water from the blood to generate urine. Nephrons stop developing near birth; thus, the number that people are born with remains static for life. However, Dr. Patel explained, some people are born with as few as 200,000 nephrons – often a consequence of premature birth or low birth weight due to maternal malnutrition – and some are born with up to 2 million.
Having fewer nephrons is a risk factor for CKD – a condition that involves gradual loss of kidney function and affects about 1 in 7 people in the U.S. – but having an overabundance of nephrons is considered protective against the disease. What causes the vast range in the number of nephrons has been unclear. If researchers could pinpoint the responsible mechanism and manipulate it, Dr. Patel said, they might be able to increase nephron numbers and enhance resilience to developing CKD.
In 2021, Dr. Patel and his colleagues discovered that methylation – a chemical modification that cells can make to RNA – plays a key role in the development of polycystic kidney disease, in which nephrons form cysts. Wondering if the same pathway might be part of normal kidney development, the researchers examined its components in healthy mice.
Working with stem cells extracted from embryonic kidneys, the researchers found that stem cells differentiating into nephrons had significantly more S-adenosylmethionine (SAM), a molecule that provides the raw materials for methylation, than stem cells that only self-renewed and didn’t form nephrons. An enzyme called METTL3, responsible for performing methylation, appeared to act as a sensor for SAM levels in these stem cells, pushing them to become nephrons when they accumulated a critical threshold of SAM.
These findings were supported by experiments using developing kidneys in petri dishes. By changing the levels of SAM supplied to the growing organs, or using a drug or genetic engineering to decrease levels of METTL3, the researchers discovered they could change the number of nephrons that developed in the tissue.
Similar manipulations in a mouse model further reinforced this idea. Mouse pups continue to grow nephrons several days after birth. Dosing them during this postnatal nephrogenesis window with SAM or a METTL3 activator drug led to significantly larger kidneys with more nephrons in adulthood than littermates that didn’t receive these interventions. Conversely, shutting down METTL3 in these pups led to atrophied kidneys with far fewer nephrons.
Additional experiments showed that a gene called Lrpprc, activated by RNA methylation, appears to play an important role in this process through supporting stem cell mitochondria, the power generators of the cell.
This is a first crucial step, and further research is needed to confirm these findings, Dr. Patel said. But the hope is that manipulating the methionine-SAM-METTL3 RNA pathway in human babies at risk of CKD due to predicted low birthweight or planned premature birth could boost their nephron numbers, he said, potentially offering a way to head off CKD before it develops.
Other UTSW researchers who contributed to this study are first author Harini Ramalingam, Ph.D., former Instructor of Internal Medicine at UT Southwestern; Thomas Carroll, M.D., Professor of Internal Medicine and Molecular Biology and Director of Basic Science Research in the Division of Nephrology; Ronak Lakhia, M.D., Assistant Professor of Internal Medicine; Jesus Alvarez, B.A., Research Assistant; Andrea Flaten, B.A., Lead Clinical Research Coordinator; Patricia Cobo-Stark, A.B., Senior Research Associate; and Elyse Grilli, M.S., Research Associate.
Dr. Patel holds the Yin Quan-Yuen Distinguished Professorship in Nephrology.
The study was funded by a grant from the National Institutes of Health (5R01DK102572).
About UT Southwestern Medical Center 
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.