Novel Mechanisms Underlying the Effect of Maternal Malnutrition on Nephrogenesis and Nephron Progenitor Cells

Background: Maternal malnutrition during pregnancy correlates with a high risk of chronic kidney disease (CKD) in adulthood, presumably by lower nephron number. We used a novel mouse model to study the effects of caloric restriction in pregnancy on kidney development and nephron progenitor cells (NPCs).

Methods: Pregnant mice were monitored in metabolic cages, and their daily caloric intake was reduced by 30% compared to the average consumption of the control group at the same gestational age. The effect on kidney morphology and function was measured by immunostaining, kidney biomarkers analysis, and nephron count. Six2 GFP NPCs were extracted from Six2 Cre E18.5 embryos of calorically restricted pregnant dams or controls and isolated by FACS. mRNA expression and metabolomic activity in sorted NPCs were evaluated by bulk RNAseq and mass spectrometry, respectively. Key findings were validated using western blotting.

Results: Animals exposed to caloric restriction in utero had 50% fewer nephrons and lower kidney function in adulthood, as demonstrated by higher serum urea levels. Calorically restricted E18.5 Six2 NPCs had decreased expression of mTOR pathway genes, and lower overall mTOR activity, reflected in lower levels of phosphorylated ribosomal protein S6. A lower proliferation rate was noted in NPCs, as well. Mass spectrometry of metabolites from isolated NPCs identified a substantial reduction in the methionine salvage pathway.

Conclusion: Reduced mTOR signaling, proliferation rate, and methionine salvage activity in NPCs from fetuses carried by malnourished mothers led to a premature end of nephrogenesis, reduced nephron numbers, and increased risk for CKD in adulthood.