Ketosis Induced Impairment of Fetal Kidney Development
Maternal ketosis during pregnancy can impact fetal development, yet its effects on kidney development are not well understood. This study investigates the impact of maternal ketosis on offspring nephrogenesis using two mouse models: a ketogenic diet and ß-hydroxybutyrate supplementation. Pregnant mice were subjected to either intervention from conception until birth. Offspring kidneys were analyzed at birth and in adulthood for nephron number, glomerular density, and renal function. Nephron progenitor cells (NPCs) were isolated from embryonic kidneys and analyzed using RNA sequencing, immunostaining, and quantitative PCR. Both ketosis models resulted in significantly reduced glomerular density at birth and a 25% decrease in nephron number in adult offspring,  accompanied by impaired renal function. RNA sequencing revealed over 1,000 differentially expressed genes in the ketogenic diet group and 164 in the ß-hydroxybutyrate group, with 67 overlapping genes. Pathway analysis showed downregulation of cell cycle and Myc target pathways, and upregulation of inflammatory pathways in both models. Immunostaining confirmed a 40% reduction in NPC proliferation and decreased c-Myc expression under ketotic conditions. Additionally, ketosis increased TNFa expression and activated the NF?B pathway in NPCs. These findings provide the first evidence linking maternal ketosis to impaired nephrogenesis, demonstrating a negative impact on offspring kidney development by altering NPC proliferation, Myc signaling, and inflammatory responses. This study highlights potential risks associated with ketogenic diets or other ketosis-inducing conditions during pregnancy. Overall design: 12 Pregnant female mice were randomly assigned to one of three regimens from conception until embryonic day E17.5: 4 were assigned a control diet, 4 were assigned a control diet with supplementation of ß-hydroxybutyrate, and 4 were assigned the ketogenic diet. On embryonic day E17.5, the embryonic kidneys from the entire litter were extracted, and the nephron progenitor cells were sorted and pooled. The RNA was extracted from the cells and sequenced. Each sample represents one litter.