Increasing mtorc1 pathway activity or methionine supplementation during pregnancy reverses the negative effect of maternal malnutrition on the developing kidney

Abstract

Background Lownephronnumber atbirth is associatedwith a highrisk ofCKDin adulthoodbecause 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 ofmalnutrition 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 associatedwith low nephron number in offspring, compromising kidney function at an older age.RNA-seqidentifiedcell cycle regulators andthemTORC1pathway, amongotherpathways, that maternal malnutrition inNPCs modifies.Metabolomics analysis ofNPCs singled out the methionine pathway as crucial forNPCproliferation andmaintenance.Methioninedeprivation reducedNPCproliferation andloweredNPC number per tip inembryonic kidney cultures,with rescue frommethionine metabolite supplementation. Importantly, in vivo, the negative effect of caloric restriction on nephrogenesiswas prevented by adding methionine to the otherwise restricted diet during pregnancy or by removing one Tsc1 allele in NPCs. Conclusions These findings show thatmTORC1 signaling andmethionine metabolismare central to the cellular and metabolic effects of malnutrition during pregnancy on NPCs, contributing to nephrogenesis and later, to kidney health in adulthood.