Abstract
There is accumulating evidence for fetal programming of later kidney disease by maternal obesity or associated conditions. We performed a hypothesis-generating study to identify potentially underlying mechanisms. Female mice were randomly split in two groups and fed either a standard diet (SD) or high fat diet (HFD) from weaning until mating and during pregnancy. Half of the dams from both groups were treated with metformin ((M), 380 mg/kg), resulting in four experimental groups (SD, SD-M, HFD, HFD-M). Caesarean section was performed on gestational day 18.5. Fetal kidney tissue was isolated from cryo-slices using laser microdissection methods and a proteomic screen was performed. For single proteins, a fold change ≥1.5 and q-value <0.05 were considered to be statistically significant. Interestingly, HFD versus SD had a larger effect on the proteome of fetal kidneys (56 proteins affected; interaction clusters shown for proteins concerning transcription/translation, mitochondrial processes, eicosanoid metabolism, H2S-synthesis and membrane remodeling) than metformin exposure in either SD (29 proteins affected; clusters shown for proteins involved in transcription/translation) or HFD (6 proteins affected; no cluster). By further analysis, ATP6V1G1, THY1, PRKCA and NDUFB3 were identified as the most promising candidates potentially mediating reprogramming effects of metformin in a maternal high fat diet.
Highlights
Pregnancy disorders threaten the well-being of mother and child and impair the normal development of the fetus
The resorption rate and litter size did not differ due to high fat diet (HFD) feeding or metformin treatment
Our study was designed to generate hypotheses on how maternal obesity and maternal metformin exposure might contribute to fetal programming of kidney disease
Summary
Pregnancy disorders threaten the well-being of mother and child and impair the normal development of the fetus. Fetal kidney development significantly depends upon sufficient supply of macro- and micronutrients and can be adversely affected by maternal malnutrition, placental dysfunction, gestational diabetes, prematurity and intrauterine stress [1]. Amongst these risk factors, maternal obesity is probably the most prevalent condition worldwide. Epidemiologic studies from the USA, England and Australia reported that about 20–30 percent of pregnant women were overweight and up to 20 percent were obese [2,3,4] These women are at higher risk to develop gestational diabetes, arterial hypertension and preeclampsia [5,6]. A significant proportion of the present pediatric population may have experienced adverse renal programming, leading to arterial hypertension and chronic renal disease during later life [1,7]
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