Andersen Louise Bjørkholt, Golic Michaela, Przybyl Lukasz, Sorensen Grith Lykke, Jørgensen Jan Stener, Fruekilde Palle, von Versen-Höynck Frauke, Herse Florian, Højskov Carsten Schriver, Dechend Ralf, Christesen Henrik Thybo, Haase Nadine
HansChristian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Experimental and Clinical Research Center, a joint cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité-Universitäsmedizin Berlin, Berlin, Germany; Department of Obstetrics, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Gynecology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
J Am Soc Hypertens. 2016 Jul;10(7):597-607.e1. doi: 10.1016/j.jash.2016.05.008. Epub 2016 Jun 4.
Maternal vitamin D deficiency is proposed as a risk factor for preeclampsia in humans. We tested the hypothesis that vitamin D depletion aggravates and high supplementation ameliorates the preeclampsia phenotype in an established transgenic rat model of human renin-angiotensin system-mediated preeclampsia. Adult rat dams, transgenic for human angiotensinogen (hAGT) and mated with male rats transgenic for human renin (hREN), were fed either vitamin D-depleted chow (VDd) or enriched chow (VDh) 2 weeks before mating and during pregnancy. Mean blood pressure was recorded by tail-cuff, and 24-hour urine samples were collected in metabolic cages at days 6 and 18 of gestation. Rats were sacrificed at day 21 of gestation. Depleted dams (VDd) had negligible serum 25-hydroxyvitamin D2+3 levels (mean ± SEM; 2.95 ± 0.45 nmol/l vs. VDh 26.20 ± 2.88 nmol/l, P = .01), but in both groups, levels of 1,25(OH)2D3 remained below detection level of 25 pmol/l. Dietary vitamin D depletion did not aggravate hypertension (mean ± SEM BP, day 20 of gestation: 151.38 ± 5.65 mmHg VDd vs. 152.00 ± 4.10 mmHg VDh) or proteinuria. Fetal anthropometrics were similar between the groups, whereas VDd displayed lower placental:fetal weight ratios (0.15 vs. 0.16 g/g, P = .01) and increased sFlt-1/PlGF ratio. Expression of hREN was lower in placenta of VDd dams (0.82 ± 0.44 AU vs. 1.52 ± 0.15 AU, P = .04). Expression of key vitamin D metabolizing enzymes was unchanged. Dietary vitamin D intervention did not alter key aspects of the preeclampsia phenotype using the transgenic rodent model of human renin-angiotensin system-mediated pre-eclampsia, plausibly due to altered vitamin D metabolism or excretion in the transgenic rats.
母体维生素D缺乏被认为是人类先兆子痫的一个风险因素。在已建立的人类肾素-血管紧张素系统介导的先兆子痫转基因大鼠模型中，我们检验了以下假设：维生素D缺乏会加重先兆子痫表型，而高剂量补充则会改善该表型。成年雌性大鼠，转人类血管紧张素原（hAGT）基因，与转人类肾素（hREN）基因的雄性大鼠交配，在交配前2周及整个孕期分别喂食维生素D缺乏饲料（VDd）或富含维生素D的饲料（VDh）。通过尾套法记录平均血压，并在妊娠第6天和第18天在代谢笼中收集24小时尿液样本。在妊娠第21天处死大鼠。维生素D缺乏组母鼠（VDd）的血清25-羟基维生素D2+3水平可忽略不计（均值±标准误；2.95±0.45 nmol/l，而VDh组为26.20±2.88 nmol/l，P = 0.01），但两组中1,25(OH)2D3水平均低于检测下限25 pmol/l。饮食中维生素D缺乏并未加重高血压（妊娠第20天的平均±标准误血压：VDd组为151.38±5.65 mmHg，VDh组为152.00±4.10 mmHg）或蛋白尿。两组间胎儿人体测量指标相似，而VDd组胎盘与胎儿体重比更低（0.15 vs. 0.16 g/g，P = 0.01），且sFlt-1/PlGF比值升高。VDd组母鼠胎盘hREN表达较低（0.82±0.44 AU vs. 1.52±0.15 AU，P = 0.04）。关键维生素D代谢酶的表达未发生变化。使用人类肾素-血管紧张素系统介导的先兆子痫转基因啮齿动物模型，饮食维生素D干预未改变先兆子痫表型的关键方面，可能是由于转基因大鼠中维生素D代谢或排泄发生了改变。
