Effect of the Intrauterine Environment of Aged Mothers on Renal Morphogenesis and Function in Mouse Offspring

Background: The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that environmental factors during fetal development—such as maternal undernutrition or aging—contribute to an increased risk of lifestyle-related diseases and chronic kidney disease (CKD) later in life. However, the underlying mechanisms remain largely unknown. In this study, we focused on advanced maternal age (AMA) pregnancy, which is becoming increasingly prevalent due to rising maternal age associated with workforce participation and advances in reproductive medicine. We aimed to elucidate how maternal aging influences nephron development and the functional maturation of the kidney in offspring. Methods: Male offspring born to Jcl:ICR female mice aged ≥6 months, mated with 10- to 16-week-old ICR male mice, were designated as the AMA group. Offspring born to 10- to 12-week-old Jcl:ICR female mice served as the control group. In both groups, phenotypic analyses from birth to adulthood—including body weight (BW), kidney weight and blood pressure (BP)—were performed. Renal morphology, gene expression, and kidney function were also examined. Results: At birth, offspring in the AMA group had significantly lower BW compared to controls. However, no difference was observed at 4 weeks (catch-up growth), and by 8 weeks, the AMA group showed significantly higher BW. Systolic BP was also significantly elevated in the AMA group. Histological analysis revealed reduced glomerular density and increased glomerular tuft area in the renal cortex of AMA offspring, suggesting glomerular hypertrophy. At birth, kidneys of the AMA group showed marked downregulation of ret, a gene essential for ureteric bud branching, along with a trend toward reduced gdnf expression. Bulk RNA sequencing of kidneys at 8 weeks revealed decreased expression of multiple genes associated with mitochondrial DNA and nuclear-encoded mitochondrial function in the AMA group. Furthermore, pathway analysis suggested suppressed oxidative phosphorylation and mitochondrial dysfunction. Conclusion: Advanced maternal age adversely affects nephron development and mitochondrial function in offspring, contributing to glomerular hypertrophy and adult-onset hypertension. These findings reinforce the DOHaD hypothesis and highlight maternal aging as a potential risk factor for future CKD in offspring. Funding: Government Support – Non-U.S.