Gillis Ellen E, Williams Jan M, Garrett Michael R, Mooney Jennifer N, Sasser Jennifer M
Department of Pharmacology and Toxicology, and.
Department of Pharmacology and Toxicology, and Department of Medicine University of Mississippi Medical Center, Jackson, Mississippi.
Am J Physiol Regul Integr Comp Physiol. 2015 Jul 1;309(1):R62-70. doi: 10.1152/ajpregu.00377.2014. Epub 2015 Apr 22.
The mechanisms of the pathogenesis of preeclampsia, a leading cause of maternal morbidity and death worldwide, are poorly understood in part due to a lack of spontaneous animal models of the disease. We hypothesized that the Dahl salt-sensitive (S) rat, a genetic model of hypertension and kidney disease, is a spontaneous model of superimposed preeclampsia. The Dahl S was compared with the Sprague-Dawley (SD) rat, a strain with a well-characterized normal pregnancy, and the spontaneously hypertensive rat (SHR), a genetic model of hypertension that does not experience a preeclamptic phenotype despite preexisting hypertension. Mean arterial pressure (MAP, measured via telemetry) was elevated in the Dahl S and SHR before pregnancy, but hypertension was exacerbated during pregnancy only in Dahl S. In contrast, SD and SHR exhibited significant reductions in MAP consistent with normal pregnancy. Dahl S rats exhibited a severe increase in urinary protein excretion, glomerulomegaly, increased placental hypoxia, increased plasma soluble fms-like tyrosine kinase-1 (sFlt-1), and increased placental production of tumor necrosis factor-α (TNF-α). The Dahl S did not exhibit the expected decrease in uterine artery resistance during late pregnancy in contrast to the SD and SHR. Dahl S pups and litter sizes were smaller than in the SD. The Dahl S phenotype is consistent with many of the characteristics observed in human superimposed preeclampsia, and we propose that the Dahl S should be considered further as a spontaneous model to improve our understanding of the pathogenesis of superimposed preeclampsia and to identify and test new therapeutic targets for its treatment.
子痫前期是全球孕产妇发病和死亡的主要原因，其发病机制部分尚未完全明确，这在一定程度上是由于缺乏该疾病的自发动物模型。我们推测，Dahl盐敏感（S）大鼠作为一种高血压和肾脏疾病的遗传模型，是一种叠加子痫前期的自发模型。将Dahl S大鼠与Sprague-Dawley（SD）大鼠（一种具有特征明确的正常妊娠的品系）以及自发性高血压大鼠（SHR，一种高血压遗传模型，尽管存在高血压但不会出现子痫前期表型）进行比较。妊娠前，Dahl S大鼠和SHR的平均动脉压（通过遥测测量）升高，但仅Dahl S大鼠在妊娠期间高血压加剧。相比之下，SD大鼠和SHR大鼠的平均动脉压显著降低，这与正常妊娠一致。Dahl S大鼠表现出尿蛋白排泄严重增加、肾小球肿大、胎盘缺氧增加、血浆可溶性fms样酪氨酸激酶-1（sFlt-1）增加以及胎盘肿瘤坏死因子-α（TNF-α）产生增加。与SD大鼠和SHR大鼠不同，Dahl S大鼠在妊娠晚期未出现预期的子宫动脉阻力降低。Dahl S大鼠的幼崽数量和窝仔数比SD大鼠少。Dahl S大鼠的表型与人类叠加子痫前期观察到的许多特征一致，我们建议进一步将Dahl S大鼠视为一种自发模型，以增进我们对叠加子痫前期发病机制的理解，并识别和测试其治疗的新靶点。
