Altered Nephron Progenitor Cell Dynamics Drive Long-Term Kidney Abnormalities Following Preterm Birth in Mice.

Preterm birth-affecting ~10% of live births globally-is associated with a markedly increased lifetime risk of chronic kidney disease (CKD), reportedly up to fivefold higher than in term births. Yet, the mechanisms linking prematurity to impaired renal development remain incompletely understood. Here, we investigated how preterm birth influences nephron endowment, kidney function, and the trajectory of kidney injury in a mifepristone-induced mouse model. We compared renal structure and function between preterm and term-born mice at postnatal day (P) 30 and P180, quantifying nephron number, glomerular morphology, and injury markers. We also performed bulk RNA sequencing on sorted nephron progenitor cells (NPCs) and non-NPC fractions from post-conception (PC) days 19.5–21.5, spanning the final window of nephrogenesis. Preterm mice exhibited up to 17% fewer nephrons at P30 (p < 0.01) and a ~25% lower kidney-to-body-weight ratio at P30 and P180 (both p < 0.05), despite a ~40% increase in body weight by P180. Injury biomarkers were elevated at P30 and P180, with serum creatinine increased by ~50%, NGAL by ~35%, urinary albumin excretion approximately doubled (p < 0.001), and KIM-1 elevated in preterm versus term controls. Glomerular density at P180 was reduced by ~30% in preterm mice; glomeruli were disproportionately localized in the medulla, and increased Bowman’s space area and capsule ratios suggested filtration defects. Transcriptomic profiling around the time of preterm birth revealed acute induction of cellular stress pathways and transiently impaired NPC differentiation that resolved within 24 hours. Concomitantly, we observed a short-lived increase in NPC proliferation and an approximate 24-hour extension of nephrogenesis, consistent with a compensatory response to bolster nephron formation and indicating a potential therapeutic window. In summary, preterm birth perturbs NPC developmental timing and stress responses, leading to reduced nephron endowment and persistent susceptibility to kidney injury.