University of Florence–led investigators report that estrogen-regulated renal progenitor cells shape pregnancy adaptation in mice with failure of estrogen receptor alpha signaling precipitating preeclampsia, maternal kidney injury, and offspring vulnerability to hypertension and chronic kidney disease.
Preeclampsia complicates ~5% of pregnancies and is associated with later-life hypertension and chronic kidney disease (CKD) for mothers and their children.
CKD affects over 10% of the global population and raises cardiovascular health risks. Males are associated with faster CKD progression, while loss of female sex hormones in postmenopausal or ovariectomized women links to higher CKD and cardiovascular events.
Researchers wanted to determine if sex differences in CKD progression might be related to kidney structural adaptations to the workload imposed by pregnancy.
In the study, “Estrogen-regulated renal progenitors determine pregnancy adaptation and preeclampsia,” published in Science, researchers used lineage tracing and single-cell RNA-sequencing to test whether estrogen signaling in renal progenitors supports podocyte generation and modulates susceptibility to glomerular injury and preeclampsia.
Animal experiments used female mice with selective estrogen receptor alpha (ER?) deletion in renal progenitors, and male mice as wild-type comparators. Human work included primary human renal progenitor cell cultures, analyses of human kidney biopsies, and urine-derived renal progenitor cultures from pregnant women but not from healthy controls.
Mouse studies showed a larger pool of renal progenitor cells after puberty, with cells moving into the kidney’s filtering units and maturing into podocytes.
In females, about one in 10 of these filters showed migrating progenitors, compared with only about one in 100 in males, and by day 120 females carried more podocytes. Removing ER? in mouse renal progenitors erased this female advantage, reduced podocyte coverage, and brought urine protein and blood pressure in line with male levels.
Human evidence mirrored those patterns. Primary renal progenitors from people exposed to 17?-estradiol and progesterone increased in number and matured more readily, with estradiol acting mainly through ER? at concentrations typical of ovulation and pregnancy. Kidney tissue from young women contained more progenitors and more podocytes than tissue from postmenopausal women or from men.
Disease models reinforced the female advantage. In chemically-induced kidney injury in mice, females showed less podocyte damage, lower protein loss in urine, and better kidney function than males. Estradiol improved outcomes in males. Loss of ER? in female progenitors reduced the appearance of new progenitor-derived podocytes.
Pregnancy experiments described expansion of kidney progenitors and new podocyte generation in wild-type dams, with reductions after ER? loss. ER?-deficient dams developed hypertension, progressive protein leakage, smaller rises in kidney filtration rate, and higher blood urea nitrogen, consistent with preeclampsia and impaired kidney function.
A comparison model that targeted blood vessel tone produced pregnancy complications of similar severity that resolved after delivery, while ER?-deficient dams remained hypertensive with chronic kidney disease.
Placentas from ER?-deficient pregnancies were smaller and more fibrotic and produced more soluble FMS-like tyrosine kinase-1. Maternal L-tryptophan fell in ER?-deficient pregnancies.
Litters were smaller, and pups were born with reduced body size and kidney weight. Offspring later developed high blood pressure and higher urinary protein by day 120, carried fewer kidney filters at birth, and showed worse injury and function after chemically induced kidney damage, with the most severe disease in males.
Authors conclude that estrogen-driven kidney progenitors expand podocyte reserves during reproductive life and pregnancy in females, lowering risks of albuminuria and hypertension.
Failure of this mechanism contributes to preeclampsia, postpartum maternal chronic kidney disease, and fewer kidney filters (nephrons) in offspring with greater lifelong vulnerability.
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More information:
Carolina Conte et al, Estrogen-regulated renal progenitors determine pregnancy adaptation and preeclampsia, Science (2025). DOI: 10.1126/science.adp4629
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