Chronic kidney disease (CKD) affects more than 10% of the global population and is expected to become the fifth leading cause of death worldwide within the next two decades. Perhaps surprisingly, women of reproductive age seem to be less susceptible to CKD than men.

Beyond the risk of kidney failure itself, CKD increases the likelihood of cardiovascular complications. Men generally face higher risks of CKD, while women in their reproductive years appear relatively protected. That discrepancy has long suggested a role for sex hormones in kidney health, but the molecular underpinnings of this protection were not well understood. An international team of researchers from Italy and Germany aimed to better understand the mechanisms driving this dichotomy between the sexes.

Their study published in Science, “Estrogen-regulated renal progenitors determine pregnancy adaptation and preeclampsia,” points to estrogen-driven regeneration of podocytes as having a protective mechanism against CKD. Further, breakdowns in this process may also underlie pregnancy complications like preeclampsia, linking maternal kidney health directly to pregnancy outcomes.

The team utilized multiple tools, combining lineage tracing, single-cell RNA sequencing, and analyses of both mouse models and human tissue and urine samples to uncover how female kidneys adapt to stress and maintain resilience against disease.

A hallmark of CKD is the depletion of podocytes, cells which do not readily divide. In mice, researchers found that females had increased regenerative ability of podocytes compared to males, a process which they found was dependent on estrogen receptor signaling.

This protective effect was amplified during pregnancy. As the kidneys expanded with increased demand throughout pregnancy, podocyte regeneration was also boosted to maintain kidney function through this highly stressful stage. In estrogen receptor α knockout (ErαKO) mice, not only did this process halt, but the pregnant mice developed preeclampsia-like symptoms, including hypertension, proteinuria, and were at increased risk of long-term complications for kidney and cardiovascular disease. Their offspring also retained long-term effects including lower birth weight, reduced kidney health and increased susceptibility to kidney disease later in life.

The findings suggest that preeclampsia may arise from a failure of renal progenitor cells to generate enough podocytes, opening the door to alternative therapeutic strategies.

The team lead, Paola Romagnani, MD, PhD, professor of Nephrology at the University of Florence, and head of Nephrology & Dialysis at AOU Meyer IRCCS spoke with GEN about their research.

This interview has been edited for length and clarity.

GEN: What was the drive behind beginning this project?

Romagnani: It began as pure serendipity. Ten years ago we tried to culture renal progenitors—the kidney’s stem cells our group had discovered—from donors’ urine. Our lab was all women; two were pregnant, and only their samples consistently grew. That couldn’t be chance. It sparked a simple idea: in pregnancy the kidney—second only to the uterus—enlarges because these progenitors expand to meet the extra workload, which may also explain women’s relative protection from CKD and hypertension. That hunch became our hypothesis.

GEN: Can you briefly describe the methods you used following the urine analysis? 

Romagnani: First, we isolated renal progenitor cells from human urine and exposed them to sex hormones. Estrogen, at ovulation and pregnancy levels, increased their proliferation and maturation; selective agonists showed this depended on ERα, and easing the proteasome “brake” further boosted differentiation.

Next, in mice, lineage tracing let us follow progenitor fate from puberty, and an RPC-specific ERα knockout let us switch off the program. In timed pregnancies we compared pregnant versus non-pregnant females to observe generation of new podocytes from RPC during pregnancy and then we compared the kidney-driven preeclampsia model (RPC-ERαKO) with an endothelial model (L-NAME) and used adriamycin and anti-GBM injury to test how sex and ERα status shaped damage and repair.

Across experiments we applied optical clearing, immunofluorescence, 3D reconstruction, and confocal and STED microscopy to quantify podocyte number/density and foot-process coverage, and single-cell RNA-seq to map progenitor states and pathways (including ribosome and ubiquitin–proteasome). To link kidney and placenta, we measured sFlt-1 and tryptophan–kynurenine metabolites. Finally, we assessed offspring birthweight, nephron endowment by 3D counts, and later blood pressure/proteinuria after injury to capture long-term consequences.

GEN: Was there a result that was exciting or unexpected? If so, how was the finding and why did you feel that way?

Romagnani: In culture, estrogens drove human renal progenitors to become podocytes, the key cells of the filtration barrier that lets the kidney cleanse the blood. To see how crucial this was, we created mouse models where the program was switched off. I expected an effect, but not this: mice unable to make new podocytes from progenitors developed preeclampsia—a leading pregnancy complication linked to ~76,000 maternal and 500,000 infant deaths worldwide each year.

GEN: Has CKD been linked to preeclampsia before?

Romagnani: Yes—the relationship runs both ways. Women with pre-existing CKD have a much higher risk of preeclampsia; conversely, women with a history of preeclampsia have increased long-term risks of hypertension and CKD, and their children carry elevated lifelong cardio-renal risk. What has been missing is a unifying renal mechanism to explain this epidemiology.

GEN: Is this all preeclampsia or a subtype?

Romagnani: Our work supports heterogeneity. We describe a kidney-driven subtype in which renal progenitors fail and renal adaptation to pregnancy breaks down. That said, the kidney is likely involved in most cases: proteinuria—a hallmark of podocyte dysfunction—occurs in the great majority (≈90%) of preeclampsia cases, even though some forms are dominated by endothelial/placental factors.

GEN: What next steps/follow-up projects are you looking forward to?

Romagnani: We’re now working to modulate this renal progenitor program in humans—first to prevent or treat the kidney-driven subtype of preeclampsia, and, more broadly, to enhance progenitor response after kidney injury and slow CKD progression. The goal is to translate a fundamental, evolution-shaped mechanism into practical prevention and therapy.

GEN: How do you envision this work translating to humans?

Romagnani: Our work identifies an evolution-shaped renal program with clear human relevance: in reproductive years, estrogens activate renal progenitors, expanding women’s renal “reserve” for pregnancy. When this program fails, adaptation collapses—preeclampsia arises—leaving mothers at risk of persistent kidney injury and children with fewer nephrons and lifelong cardio-renal risk. Translationally, this clarifies sex differences in CKD/hypertension and a kidney-driven subset of preeclampsia, and supports human studies to measure kidney reserve, refine risk stratification, and improve pre-, peri-, and postpartum monitoring for mothers and children.

GEN: Is there anything else you would like to share about your work or team?

Romagnani: This study is the result of a decade of patient, quiet work that involved the whole team but particularly that of the first author, Carolina Conte, PhD, that I would like to acknowledge. When we understood we were witnessing the kidney’s evolutionary adaptation to pregnancy, it was scientifically compelling and personally moving to understand the elegance of a mechanism that sustains fetal growth while protecting the mother’s kidneys. I’m deeply grateful to the entire group for their rigor and perseverance.