MATERNAL AGING IMPAIRS FETAL NEPHROGENESIS AND POSTNATAL MITOCHONDORIAL HEALTH: INSIGHTS FROM A MOUSE MODEL OF ADVANCED MATERNAL AGE

Advanced maternal age (AMA), defined as pregnancy at 35 years or older, has been increasing worldwide due to the trend toward women’s social advancement. AMA is considered a high-risk pregnancy, as it is associated with a higher incidence of a greater rate of low birth weight (LBW) infants. LBW is known to be associated with a reduced number of nephrons, which contributes to the development of hypertension (HT) and chronic kidney disease (CKD) later in life. In addition, recent studies have suggested that the risk of CKD associated with intrauterine environmental factors may not be limited to nephron number but may also involve the postnatal functional maturation of the kidney; however, the molecular basis remains poorly understood. This study aimed to elucidate how maternal aging affects renal development and postnatal renal phenotypes, using a mouse model of AMA.

Female Jcl:ICR mice aged ≥6 months were mated with 10–16-week-old males to generate the AMA group, while offspring from 10–12-week-old females served as controls. Male offspring were evaluated from birth to adulthood for body weight (BW), kidney weight, and systolic blood pressure (BP), and urinary protein excretion. Morphometric analyses were performed to quantify cortical glomerular density and glomerular tuft area. Gene expression analyses were conducted using neonatal kidneys to assess genes related to ureteric bud (UB) branching and mesenchymal markers. In 8-week-old kidneys, bulk RNA sequencing was performed to comprehensively analyze gene expression changes. Metabolomic profiling of kidney tissue was also performed to evaluate alterations in metabolic pathways.

Offspring from AMA mothers exhibited significantly lower BW at birth (p < 0.01), followed by catch-up growth by 4 weeks and increased BW and systolic BP at 8 weeks (obese and HT) (p < 0.05). Kidney weight did not differ between groups; however, histological analysis revealed a significantly lower cortical glomerular density and a larger glomerular tuft area in the AMA group. At birth, renal expression of genes associated with UB branching-related genes such as Gdnf and Ret was significantly reduced. In 8-week-old kidneys, bulk RNA-sequencing analysis demonstrated decreased expression of multiple mitochondrial and nuclear genes related to mitochondrial function. Gene set enrichment analysis revealed marked downregulation of pathways related to mitochondrial function and oxidative phosphorylation, accompanied by upregulation of angiogenesis-related gene sets. Metabolomic profiling of the kidneys indicated activation of purine, amino acid, and nucleotide metabolism, with elevated levels of AMP and IMP. In addition, fatty acid–derived acetyl-CoA was increased, whereas TCA cycle intermediates were decreased, suggesting impaired TCA cycle turnover and metabolic reprogramming secondary to mitochondrial dysfunction. 

Maternal aging alters the intrauterine environment, suppressing UB branching and nephron formation during kidney development and subsequently impair postnatal mitochondrial function and metabolic maturation, leading to glomerular hypertrophy, adult-onset HT and obesity. These findings suggest that maternal aging may represent a potential risk factor for the future development of CKD in offspring, supporting the concept of DOHaD.