Malnutrition During Pregnancy Impairs Nephrogenesis by Interrupting Methionine Metabolism

Background: Poor nutritional status during pregnancy has long term effects on kidney health by impairing nephron endowment in an unknown mechanism. Nephron progenitor cells are dependent on constant nutrient supply for maintaining high metabolic activity. We aimed to study the effect of malnutrition during pregnancy on the metabolic profile of nephron progenitor cells. Methods: Six2 Cretg/+ males were mated with wild type females. Pregnant mice were fed with 70% of the daily chaw intake in individual cages. Six2+ NPC’s cells were FACS sorted and the metabolites were extracted and measured using mass spectrometry. For kidney organ cultures, kidneys were dissected and immediately incubated in well plates containing media either with or without L-methionine. By the end of the incubation period, the kidneys were fixed and whole-mount immunostained for Six2 and cytokeratin (ureteric bud marker). The nephron number was measured by acid maceration. Results: The metabolomic analysis showed significant impairment in methionine metabolism in E15.5 NPCs. Methionine deprivation in organ culture reduced nephron progenitors’ density in metanephric mesenchyme of cultured embryonic kidneys. The effect was reversible by supplementation of the media without L-methionine, with metabolites that promote methionine recycling. Supplementation of methionine-enriched drinking water to caloric restricted pregnant mice prevented the reduction in nephron number in offspring. Conclusions: Impairment of methionine metabolism plays a major role in mediating the effect of caloric restriction on kidney development. Replenishing methionine may revert the effect of malnutrition on the future risk of developing chronic kidney disease in offspring.