Role of Elevated SFLT‐1 on the Regulation of Placental Transporters in Women With Pre‐Eclampsia

Abstract

Pre-eclampsia (PE) is an obstetric complication associated with elevated levels of fms-like tyrosine kinase 1 (sFlt-1) and dysregulated trophoblast differentiation. However, limited information exists on the expression and regulation of placental drug transporters in PE. Transporter mRNA and protein expression were analyzed in human placentas diagnosed with PE (n = 34) and gestational age-matched controls (n = 24), whereas placental BeWo cells were treated with angiogenic factors in vitro. Significant downregulation of breast cancer resistance protein (BCRP) and several other transporters were seen in placentas complicated by PE compared with controls, whereas mRNA levels of sFlt-1 were induced by 2.5-fold in PE placentas (P < 0.01). Treatment of BeWo cells with sFlt-1 resulted in an 85-90% downregulation of BCRP, which was attenuated by vascular endothelial growth factor. Our findings suggest that placental function is compromised during PE due to altered expression of clinically important transporters. Furthermore, our in vitro results show that sFlt-1 is involved in the regulation of BCRP.

Organic Anion Transporting Polypeptide 2B1 in Human Fetal Membranes: A Novel Gatekeeper for Drug Transport During Pregnancy?

“…In our study, OATP2B1 expression remained unaffected following CSE treatment, whereas in the placental explants OATP2B1 decreased in a time-dependant manner following CSE treatment. This finding is contrary to previous findings (Kojovic et al, 2020), where OATP2B1 expression was increased in preeclamptic placentae (Kojovic et al, 2020). This could be due to differences between explant phenotypes used, as Kojovic et al, utilized placental tissues obtained from preeclamptic women and here cesarian-derived placental explants were stimulated with CSE.…”

“…Interestingly, oxidative stress and inflammation can also affect OATP2B1 expression (Kojovic et al, 2020). For example, a study by Kojovic et al, reported that OATP2B1 expression was increased in placentae obtained from women with preeclampsia (a pregnancy-specific disorder often characterized by increased oxidative stress and increased proinflammatory cytokines) (Kojovic et al, 2020). An alteration in the expression of functionally essential transporters (such as OATP2B1) suggests that placental function is compromised during pregnancy complications.…”

Regulation of Placental Efflux Transporters during Pregnancy Complications

“…Interestingly, exposure of human BeWo trophoblast cells to sFlt-1 reduces BCRP expression by 85 to 90% which can be rescued by vascular endothelial growth factor. These findings may be important in understanding transporter regulation during pre-eclampsia (Kojovic et al, 2020b). Epigenetic factors may also play a role in transporter regulation during disease.…”

“…In general, placentas from pre-eclamptic pregnancies tend to exhibit reduced transporter expression when evaluated by microarray (Herse et al, 2007;Nishizawa et al, 2007;Founds et al, 2009;Pantham et al, 2012;Vaiman et al, 2013;Gormley et al, 2017). Additional studies where mRNA and protein expression were quantified confirm that pre-eclampsia is often associated with reduced expression of placental MDR1, MRP1, 2, and BCRP transporters though some transporters are unchanged or slightly increased (Afrouzian et al, 2018;Kojovic et al, 2020b). When pre-eclampsia is severe and early in its onset, a prominent reduction in placental MDR1 protein expression has been observed (Dunk et al, 2018).…”

Impact of Th-17 Cytokines on the Regulation of Transporters in Human Placental Explants

“…The mRNA expression of BCRP, OAT4, OATP2B1, and OCT3 was determined in the treated and untreated (control) explants, using qRT-PCR, as previously described [21]. In brief, RNA was extracted from placental explants using Trizol (Invitrogen, Carlsbad, CA, USA) and total RNA concentrations were quantified using the NanoDrop 1000 spectrometer (Thermo Fisher Scientific.…”