Estrogen supports kidney regeneration and protects women from chronic disease

A new study in mice provides insights into why females in their reproductive years appear to be relatively protected from chronic kidney disease, a leading public health concern. The study reports that estrogen-regulated signaling promotes the regeneration of key filtration cells in female kidneys. The study also links pregnancy complications like preeclampsia to failures in this regenerative process. Chronic kidney disease (CKD) – which affects more than 10% of the global population – is a leading public health concern, not only because it can lead to fatal kidney failure, but also because it increases the risk of cardiovascular disease. Within the next 20 years, CKD is expected to become the fifth leading cause of death globally.

Previous research has shown that sex differences play a notable role in disease progression: men are at higher risk for CKD, while women of reproductive age appear to be relatively protected. Although this suggests that female sex hormones, like progesterone and estrogen, may have a protective effect in the development of CKD, the mechanisms underlying the observed sex-based differences in disease susceptibility remain poorly understood.

Through lineage tracing, single-cell RNA sequencing, and an analysis of mouse models and human tissue and urine samples, Carolina Conte and colleagues show that female kidneys possess a greater capacity to regenerate key filtering cells, called podocytes, from renal progenitor cells. The cells are regenerated through estrogen receptor–dependent signaling, which protects against kidney disease and hypertension during reproductive years. What's more, the authors found that this effect intensified in pregnant mice as kidneys adapted to a higher workload. However, when this regenerative capability is compromised, such as in preeclampsia, mouse mothers face heightened long-term risks of kidney disease and hypertension. At the same time, their offspring are predisposed to poor nephron development, low birth weight, and later-life cardiovascular and renal problems.

According to Conte et al., the findings indicate that preeclampsia may arise from a failure of kidney progenitor cells to supply sufficient podocytes, linking maternal kidney health directly to pregnancy outcomes. This link offers new insights into potential therapeutic opportunities.