Novel Mechanisms of Preeclampsia Prevention via SGK1

Carolyn C Lo; Sabrina M Scroggins; Eric J Devor; Donna A Santillan; Mark K Santillan

doi:10.1096/fasebj.2019.33.1_supplement.865.10

Preeclampsia (PE), a hypertensive disorder of pregnancy, involves poor trophoblast invasion, poor spiral artery remodeling, and an early systemic inflammatory immune response. In the chronic infusion of vasopressin (AVP) mouse model of PE, the mice showed similar obstetric and immune alterations observed in humans. We have shown that a single dose of betamethasone (BMTZ) early in pregnancy in AVP infused dams will reverse pregnancy‐induced hypertension and proteinuria. However, the mechanism of this reversal is still unclear. SGK1 is a serine/threonine kinase that is stimulated by BMTZ. SGK1 dysregulation, as well as human genetic variants in SGK1, have been implicated in the development of hypertension through a decrease in the anti‐inflammatory TH2 renal milieu. Further SGK1−/− mice exhibit fetal growth restriction and demise via this pro‐inflammatory shift leading to decidual apoptosis and poor trophoblast invasion, a feature well demonstrated in PE. Further, miR365 has been shown to decrease SGK‐1 expression in human deciduas from pregnancies with poor placentation. Together, these data suggest BMTZ reverses AVP‐induced preeclampsia via upregulation of SGK1 in mice, and that human preeclamptic women have a reduced expression of SGK1 via regulation by miR365. Thus, we hypothesized that AVP and SGK1 regulate the expression of miR365 in placental cells, playing a role in the development of preeclampsia. To address our hypothesis, we utilized primary placental tissues and HTR8/SVneo trophoblast cells to examine the expression of miR365 and SGK1. Placental tissues were used to determine if miR‐365a‐3p is differentially expressed in human preeclampsia. Human preeclamptic and non‐preeclamptic samples were obtained from the Maternal Fetal Tissue Bank (MFTB) (IRB# 200910784) at the University of Iowa. HTR8/SVneo cells were treated for 24 hours with either saline, AVP (300ng/mL), AVP+BMTZ (10−4 mM), AVP+SGK1 inhibitor (1mM), or AVP+BMTZ+SGK1 inhibitor. Quantitative real‐time PCR was used to measure miR365 and SGK1. In primary placental tissues, there is a 1.5‐fold lower expression of miR365 in preeclamptic compared to non‐preeclamptic samples (p=0.016, n=20). Although, there was no difference in expression of SGK1 in tissues from preeclamptic versus non‐preeclamptic (p>0.05, n=20) placentas. HTR8/SVneo cells showed no difference in the expression of miR365 (p>0.05, n=4) between different treatments. No difference was observed in the expression of SGK1 in HTR8/SVneo treated cells (p>0.05, n=4). These findings support the conclusion that miR365 is differentially expressed in preeclamptic placental tissues versus non‐preeclamptic placental tissues. Additionally, treatments with AVP, BMTZ, and/or SGK1 inhibitor does not change the expression of SGK1 and miR365. Our data suggest the reduced expression of miR365 observed in preeclamptic pregnancies is mediated via an SGK1 independent mechanism. Support or Funding Information Funding provided by The American Physiological Society STRIDE fellowship (CL), American Heart Association Strategically Focused Research Network in Hypertension (MS, JG, SS, DS), American Heart Association Postdoctoral Fellowship (SS). This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.

Novel Mechanisms of Preeclampsia Prevention via SGK1

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