589 - Maternal Low Nephron Number Predisposes Offspring to Adverse Renal Outcomes

Publication Number: 589.6030

Ryota Kobayashi, Department of Pediatrics, the Jikei University School of Medicine, Minatoku, Tokyo, Japan; Yuka Inage, The Jikei University School of Medicine, Tokyo, Tokyo, Japan; Kei Matsumoto, The JIKEI University, Minato-Ku, Tokyo, Japan; Daishi Hirano, The Jikei university school of medicine, Ohta-ku, Tokyo, Japan; Kimihiko Oishi, The Jikei University School of Medicine, Tokyo, Tokyo, Japan

Background: Human nephrogenesis is complete by 36 weeks of gestation, with no further nephron formation occurring postnatally. This developmental limitation makes preterm infants susceptible to low nephron number (LNN). Epidemiological evidence demonstrates that women with a history of preterm birth or low birth weight have significantly elevated risks for gestational hypertension and preeclampsia, though underlying mechanisms remain unclear. It may negatively impact their offspring. We hypothesized that maternal LNN, resulting from premature birth, could contribute to adverse renal outcomes in offspring. Recently, we developed a genetically modified mouse model with LNN.

Objective: To characterize the impact of maternal LNN on renal function in offspring using a genetically modified mouse model with LNN.

Design/Methods: An LNN mouse model was generated by crossing mice expressing Cre recombinase in nephron progenitor cells under Six2 promoter control with loxP-diphtheria toxin receptor transgenic mice. Diphtheria toxin was administered at embryonic day 13.5 to inhibit fetal nephrogenesis selectively. Female LNN and wild-type control mice were divided into two dietary groups: a standard diet (ND, NaCl 0.8%) and a high-salt diet (HSD, NaCl 4%), starting at 3 weeks of age. After 8 weeks on these diets, they were mated with wild-type males. Offspring kidney function was evaluated at 4 weeks postnatally.

Results: Offspring born to HSD-fed LNN mice exhibited markedly elevated serum BUN levels at four weeks compared to controls born to HSD-exposed wild-type control mice (95% CI, 9.13-46.9, p=0.002). Additionally, offspring of HSD-fed LNN mice showed a trend towards fewer glomeruli per renal cross-sectional area (/mm²) compared to other groups (median glomerular counts: offspring of HSD-fed LNN mice: 4.26 (3.99-4.79), offspring of ND-fed LNN mice: 5.24 (5.08-5.43), offspring of HSD-fed control mice: 5.65 (5.11-6.00)), while statistical significance was not achieved.

Conclusion(s): Our findings suggest that maternal LNN may increase the risk of renal dysfunction in offspring. Furthermore, HSD appears to negatively affect nephrogenesis in the offspring of females with LNN. These results indicate that dietary interventions, such as avoiding HSD during pregnancy, may be beneficial for women who were born preterm, given their susceptibility to LNN due to underdeveloped nephrons.