Gestational Ketosis Compromises Nephron Endowment and Long-Term Kidney Function in Offspring

Area of Science:

• Reproductive biology
• Developmental biology
• Nephrology

Background:

• Ketogenic diets are increasingly popular, raising safety concerns during pregnancy.
• While mild ketosis is normal in pregnancy, the effects of diet-induced ketosis on fetal kidney development are unknown.
• This study investigates maternal ketosis' impact on offspring nephrogenesis and long-term kidney outcomes.

Purpose of the Study:

• To determine the effects of maternal ketosis on fetal kidney development and nephrogenesis.
• To assess the long-term kidney function in offspring exposed to maternal ketosis.
• To elucidate the molecular mechanisms underlying ketosis-induced nephrogenesis disruption.

Main Methods:

• Utilized two murine models: maternal ketogenic diet and β-hydroxybutyrate supplementation throughout gestation.
• Assessed offspring kidney structure and function via nephron counts, kidney size, and serum markers.
• Examined nephron progenitor cell (NPC) dynamics using transcriptomics, immunostaining, and qPCR.

Main Results:

• Both ketogenic diet and β-hydroxybutyrate supplementation reduced offspring nephron number and impaired kidney function.
• Transcriptomic analysis revealed suppressed cell-cycle and Myc signaling, with activated inflammatory pathways (TNFα/NFκB) in NPCs.
• Reduced NPC proliferation and c-Myc, increased TNFα expression, and insufficient postnatal recovery confirmed a nephron deficit.

Conclusions:

• Maternal ketosis disrupts fetal kidney development by suppressing c-Myc signaling and activating NPC inflammation.
• This leads to a congenital nephron deficit and compromised adult kidney function.
• Findings highlight potential risks of ketogenic diets during pregnancy for offspring kidney health.