Yaniv Makayes1, Elad Resnick1, Liad Hinden2, Elina Aizenshtein3, Tomer Shlomi3, Raphael Kopan4, Morris Nechama1,5, Oded Volovelsky6,5. 1. Pediatric Nephrology Unit and Research Lab, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel. 2. Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel. 3. Faculty of Biology, Technion, Haifa, Israel. 4. Division of Developmental Biology, Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Wohl's Translation Research Institute at Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 6. Pediatric Nephrology Unit and Research Lab, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel odedvo@hadassah.org.il.
Abstract
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.
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.
Authors: Chantal C Hoppe; Roger G Evans; John F Bertram; Karen M Moritz Journal: Am J Physiol Regul Integr Comp Physiol Date: 2007-02-01 Impact factor: 3.619
Authors: T Q Henry; R Z Mansano; C C Nast; J Lakshmanan; M Abdallah; A K Abdel-Hakeem; M Desai; M G Ross; T R Magee Journal: J Dev Orig Health Dis Date: 2010-02 Impact factor: 2.401
Authors: Dana M Gwinn; David B Shackelford; Daniel F Egan; Maria M Mihaylova; Annabelle Mery; Debbie S Vasquez; Benjamin E Turk; Reuben J Shaw Journal: Mol Cell Date: 2008-04-25 Impact factor: 17.970