Use of Traditional and Proteomic Methods in the Assessment of a Preclinical Model of Preeclampsia.

ABSTRACT

Recent studies have demonstrated downregulation of breast cancer resistance protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). BCRP is highly expressed in placenta and plays an important role in preventing xenobiotics from entering the fetal compartment. Although PE is often therapeutically managed with drugs that are substrates of BCRP, there are limited studies on the impact of PE on fetal drug exposure. Due to ethical concerns, use of preclinical models is an important approach. Thus, by using proteomic and traditional methods, we characterized transporter changes in an immunologic rat model of PE to determine its utility and predictive value for future drug disposition studies. PE was induced by daily administration of low-dose endotoxin (0.01-0.04 mg/kg) to rats on gestational days (GD) 13-16, urine was collected, and rats were sacrificed on GD17 or GD18. PE rats shared similar phenotype to PE patients, including proteinuria, and increased levels of tumor necrosis factor α and interleukin 6. Transcript and protein levels of Bcrp were significantly downregulated in placenta of PE rats on GD18. multidrug resistance 1a, multidrug resistance 1b, and organic anion transporting polypeptide 2B1 mRNA were also decreased in PE. Proteomics revealed activation of various hallmarks of PE including immune activation, oxidative stress, endoplasmic reticulum stress and apoptosis. Overall, our results demonstrated that the immunologic PE rat model exhibits numerous similarities to human PE along with dysregulation of placental transporters. Therefore, this model may be useful in examining the impact of PE on the maternal and fetal disposition of BCRP substrates. SIGNIFICANCE STATEMENT Fully characterizing preclinical models of disease is necessary to determine their validity to human conditions. Combining traditional and proteomic methods of model characterization, we identified numerous phenotypic similarities between our model of preeclampsia and human disease. The alignment with human pathophysiological changes allows for more confident use of this preclinical model.