Fetal growth restriction leads to prolonged nephrogenesis and persistent developmental gene dysregulation in the adult kidney

Introduction: Low birthweight is a risk factor for chronic kidney disease (CKD), in part due to an associated low nephron number, but the mechanisms leading to increased risk are not well understood. Low birthweight and growth restriction can be modeled in mice using gestational low protein (LP). Using this model, here we sought to 1) identify a potential window for therapeutic intervention to prevent future CKD in LP animals, 2) understand the transcriptional impact of LP on adult kidneys, and 3) clarify the mechanistic connection between low nephron endowment and predisposition to disease in LP animals. We hypothesized that gestational LP-induced growth restriction would lead to shorter nephrogenesis and altered gene expression in adulthood. Methods: At the initiation of pregnancy, CD-1 dams received a normal protein (NP, 18%) or LP (8%) diet. Offspring were euthanized on postnatal days (PN) 2-7 (n=2-7/day). Kidneys were stained with Periodic acid–Schiff (PAS). Immunofluorescence was used to assess SIX2 (progenitor cells), JAG1 (nascent nephron patterning), and LEF1 (Wnt signaling). At 6 weeks, mice underwent transdermal glomerular filtration rate (GFR) measurement. Ex vivo kidneys underwent histologic evaluation, bulk RNA sequencing, and cationic ferritin- enhanced MRI to quantify glomerular number (Nglom). Results: LP mice had protracted nephrogenesis extending to PN5-6, compared to NP mice that had completed nephrogenesis by PN3-5. Adult LP mice had fewer glomeruli, and LP males had lower GFR and more ATG compared to NP males. LP mice did not have evidence of glomerular hypertrophy. In LP males, the following genes were downregulated: Gfr1, Pax8, Fgf10, Dvl1, and Aldh1a1. Foxd1, Hif1an, Egln3, and Fzd7 were upregulated in the LP males. LP females exhibited upregulation of Etv5 and Osr2 and downregulation of Gata3, Mgp, and Trpv6 with no overlap of dysregulated genes between the sexes. Conclusions: LP offspring exhibit prolonged nephrogenesis and a reduced nephron endowment in adulthood. In males, this is characterized by a suppressed retinoic acid–GDNF–Wnt axis, while both sexes show persistent dysregulation of developmental genes. Together, these findings identify the late gestational and early postnatal periods as critical therapeutic windows. Targeting these molecular pathways during active nephrogenesis may offer a strategy to mitigate the programmed risk of CKD in growth-restricted offspring.