Pediatric Nephrology Unit and Research Lab, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.
J Am Soc Nephrol. 2021 Aug;32(8):1898-1912. doi: 10.1681/ASN.2020091321. Epub 2021 May 6.
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).
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.
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.
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.
出生时的肾小球数量较少与成年后发生 CKD 的风险较高相关，因为肾发生在此时已经完成。宫内环境较差会损害肾小球的先天发育，但其具体的分子机制尚不清楚。本研究采用限制热量饮食（CRD）的小鼠模型来探讨孕期营养不良对肾祖细胞（NPC）的影响。
在孕期每天减少 30%的热量摄入，然后对分离出的 Six2 NPC 进行 mRNA 表达、细胞周期和代谢活性的评估。通过转染小鼠、口服营养补充和器官培养对结果进行验证。
孕期 CRD 会导致后代肾小球数量减少，进而导致其老年时肾功能受损。RNA-seq 发现，除其他通路外，细胞周期调节因子和 mTORC1 通路在 NPC 中受到母体营养不良的调节。NPC 的代谢组学分析突出了蛋氨酸途径对 NPC 增殖和维持的重要性。蛋氨酸剥夺会降低 NPC 的增殖能力，并减少胚胎肾培养物中每个顶端的 NPC 数量，而添加蛋氨酸代谢物则可以挽救这种减少。重要的是，在孕期限制饮食中添加蛋氨酸或敲除 NPC 中的一个等位基因，可预防热量限制对肾发生的负面影响。
这些发现表明，mTORC1 信号和蛋氨酸代谢是孕期营养不良对 NPC 产生细胞和代谢影响的关键因素，这些影响可导致肾发生，并进而影响成年后的肾脏健康。
