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Ketosis Induced Impairment of Fetal Kidney Development

ABSTRACT: Maternal ketosis during pregnancy can impact fetal development, yet its effects on kidney development are not well understood. This study investigates the impact of maternal ketosis on offspring nephrogenesis using two mouse models: a ketogenic diet and β-hydroxybutyrate supplementation. Pregnant mice were subjected to either intervention from conception until birth. Offspring kidneys were analyzed at birth and in adulthood for nephron number, glomerular density, and renal function. Nephron progenitor cells (NPCs) were isolated from embryonic kidneys and analyzed using RNA sequencing, immunostaining, and quantitative PCR. Both ketosis models resulted in significantly reduced glomerular density at birth and a 25% decrease in nephron number in adult offspring, accompanied by impaired renal function. RNA sequencing revealed over 1,000 differentially expressed genes in the ketogenic diet group and 164 in the β-hydroxybutyrate group, with 67 overlapping genes. Pathway analysis showed downregulation of cell cycle and Myc target pathways, and upregulation of inflammatory pathways in both models. Immunostaining confirmed a 40% reduction in NPC proliferation and decreased c-Myc expression under ketotic conditions. Additionally, ketosis increased TNFα expression and activated the NFκB pathway in NPCs. These findings provide the first evidence linking maternal ketosis to impaired nephrogenesis, demonstrating a negative impact on offspring kidney development by altering NPC proliferation, Myc signaling, and inflammatory responses. This study highlights potential risks associated with ketogenic diets or other ketosis-inducing conditions during pregnancy.

ORGANISM(S): Mus musculus

PROVIDER: GSE274301 | GEO | 2024/11/10

REPOSITORIES: GEO

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Project description:Preterm neonates are at high risk for nephron loss under adverse clinical conditions (e.g., cardiocirculatory decompensation, nephrotoxic drugs). Importantly, the onset of renal damage potentially collides with the proceeding nephrogenesis of prematurity prior 36 weeks of gestation. Recent animal studies suggest that early nephron loss within this vulnerable phase is associated with more severe glomerular and tubulointerstitial alterations later in life, irrespective of the occurrence of arterial hypertension. It is known that nephrogenic pathways are reactivated after acute kidney injury supporting renal repair and regeneration. In this study we hypothesized that nephron loss during nephrogenesis leads to an alteration of the kidney developmental program which in turn impairs homeostasis and repair and thus aggravates kidney injury later in life. Preterm infants prior to 36 weeks of gestation show an active nephrogenesis after birth. In rats, nephrogenesis is still active until day 10 of life. Mimicking the human situation of acute nephron loss in preterm neonates with ongoing nephrogenesis, rats were uninephrectomized at day 1 of life (UNXd1). A second group of animals was uninephrectomized at day 14 of life (UNXd14), which resembles a nephron loss after terminated nephrogenesis. Age-matched control groups were sham operated. Three days after uninephrectomy the animals were sacrificed. Transcriptional renal changes were analyzed by RNAseqencing, followed by in silico functional pathway analysis. In UNXd1 animals 1182 genes were differentially regulated compared to the respective control group. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations in UNXd1 animals. Reduced expression levels of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and kidney injury (nephrin, podocin, Tgf-β1) were detected in the kidney of UNXd1 animals. The downregulation of Bmp7 and Gdnf expression in the remaining kidney of UNXd1 animals persisted until day 28 of life. In UNXd14 rats Six2 was upregulated and Pax22 downregulated compared to controls. We conclude that neonatal nephron loss during active nephrogenesis affects renal development and induces persistently reduced expression levels of genes which in turn might hinder tissue repair after kidney injury later in life.

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Ketosis Induced Impairment of Fetal Kidney Development

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