Background: Low nephron number at birth is associated with a high risk of CKD in adulthood because nephrogenesis is completed . Poor intrauterine environment impairs nephron endowment 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, , the negative effect of caloric restriction on nephrogenesis was prevented by adding methionine to the otherwise restricted diet during pregnancy or by removing one 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455268PMC
http://dx.doi.org/10.1681/ASN.2020091321DOI Listing

Publication Analysis

Top Keywords

mtorc1 pathway
8
maternal malnutrition
8
low nephron
8
nephron number
8
malnutrition pregnancy
8
cell cycle
8
npc proliferation
8
methionine
6
pregnancy
5
increasing mtorc1
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!