Estrogen-regulated renal progenitors determine pregnancy adaptation and preeclampsia

Abstract

The global burden of kidney disease displays marked sexual dimorphism. Lineage tracing and single-cell RNA-sequencing revealed that starting from puberty, estrogen signaling in female mice supports self-renewal and differentiation of renal progenitors to increase filtration capacity, reducing sensitivity to glomerular injury compared with that of males. This phenomenon accelerated as female kidneys adapted to the workload of pregnancy. Deletion of estrogen receptor α in renal progenitors disrupted this adaptation, leading to preeclampsia, fetal growth restriction, and increased maternal risk of hypertension and chronic kidney disease. Offspring from affected mothers had fewer nephrons, resulting in early-life hypertension and greater susceptibility to kidney disease. These results highlight the fundamental role of kidney fitness and renal progenitors for pregnancy and preeclampsia and as a determinant of sexual dimorphism in kidney disease.