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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE316576 | GEO | 2026/04/17

REPOSITORIES: GEO

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Project description:Preterm neonates are at high risk for nephron loss under adverse clinical conditions (e.g., cardiocirculatory decompensation, nephrotoxic drugs). Importantly, the onset of renal damage potentially collides with the proceeding nephrogenesis of prematurity prior 36 weeks of gestation. Recent animal studies suggest that early nephron loss within this vulnerable phase is associated with more severe glomerular and tubulointerstitial alterations later in life, irrespective of the occurrence of arterial hypertension. It is known that nephrogenic pathways are reactivated after acute kidney injury supporting renal repair and regeneration. In this study we hypothesized that nephron loss during nephrogenesis leads to an alteration of the kidney developmental program which in turn impairs homeostasis and repair and thus aggravates kidney injury later in life. Preterm infants prior to 36 weeks of gestation show an active nephrogenesis after birth. In rats, nephrogenesis is still active until day 10 of life. Mimicking the human situation of acute nephron loss in preterm neonates with ongoing nephrogenesis, rats were uninephrectomized at day 1 of life (UNXd1). A second group of animals was uninephrectomized at day 14 of life (UNXd14), which resembles a nephron loss after terminated nephrogenesis. Age-matched control groups were sham operated. Three days after uninephrectomy the animals were sacrificed. Transcriptional renal changes were analyzed by RNAseqencing, followed by in silico functional pathway analysis. In UNXd1 animals 1182 genes were differentially regulated compared to the respective control group. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations in UNXd1 animals. Reduced expression levels of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and kidney injury (nephrin, podocin, Tgf-β1) were detected in the kidney of UNXd1 animals. The downregulation of Bmp7 and Gdnf expression in the remaining kidney of UNXd1 animals persisted until day 28 of life. In UNXd14 rats Six2 was upregulated and Pax22 downregulated compared to controls. We conclude that neonatal nephron loss during active nephrogenesis affects renal development and induces persistently reduced expression levels of genes which in turn might hinder tissue repair after kidney injury later in life.

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

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