Increasing mTORC1 Pathway Activity or Methionine Supplementation during Pregnancy Reverses the Negative Effect of Maternal Malnutrition on the Developing Kidney

Significance Statement Kidney development ceases at the end of the third trimester of pregnancy, with no new nephrons forming after birth even with numerous injuries. Therefore, the intrauterine environment, as the maternal nutritional state, has a high effect on the risk of kidney disease when the fetus reaches adulthood. Impairment of mTOR pathway activity and methionine metabolism in nephron progenitor cells play a pivotal role in mediating the effect of caloric restriction during pregnancy on nephron endowment in a mouse model. Increasing the activity of the mTOR pathway or methionine supplementation during pregnancy reverses the negative effect of maternal malnutrition on the developing kidney. These results highlight new interventions to improve nephrogenesis in high-risk pregnancies. Background Low nephron number at birth is associated with a high risk of CKD in adulthood because nephrogenesis is completed in utero . Poor intrauterine environment impairs nephron endowment via an undefined molecular mechanism. A calorie-restricted diet (CRD) mouse model examined the effect of malnutrition during pregnancy on nephron progenitor cells (NPCs). Methods Daily caloric intake was reduced by 30% during pregnancy. mRNA expression, the cell cycle, and metabolic activity were evaluated in sorted Six2 NPCs. The results were validated using transgenic mice, oral nutrient supplementation, and organ cultures. Results Maternal CRD is associated with low nephron number in offspring, compromising kidney function at an older age. RNA-seq identified cell cycle regulators and the mTORC1 pathway, among other pathways, that maternal malnutrition in NPCs modifies. Metabolomics analysis of NPCs singled out the methionine pathway as crucial for NPC proliferation and maintenance. Methionine deprivation reduced NPC proliferation and lowered NPC number per tip in embryonic kidney cultures, with rescue from methionine metabolite supplementation. Importantly, in vivo , the negative effect of caloric restriction on nephrogenesis was prevented by adding methionine to the otherwise restricted diet during pregnancy or by removing one Tsc1 allele in NPCs. Conclusions These findings show that mTORC1 signaling and methionine metabolism are central to the cellular and metabolic effects of malnutrition during pregnancy on NPCs, contributing to nephrogenesis and later, to kidney health in adulthood.