title: The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Gillis
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, and Department of Medicine University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garrett
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Mooney
authors.affiliation: Department of Pharmacology and Toxicology, and jsasser@umc.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sasser
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011225:Pre-Eclampsia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D011507:Proteinuria / Q000235:genetics / Q000503:physiopathology; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR; D013045:Species Specificity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055988:Uterine Artery / Q000503:physiopathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014655:Vascular Resistance
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: HIF-1α; TNF-α; animal model; hypertension; pregnancy; proteinuria; sFLT-1; superimposed preeclampsia; uterine artery resistance