The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

The effects of placental miRNAs predicted to target the placental renin-angiotensin system on trophoblast proliferation (#58)

Anya L Arthurs 1 , Sarah J Delforce 1 , Eugenie R Lumbers 1 , Kirsty G Pringle 1
  1. University of Newcastle, Newcastle, NSW, Australia

Placental development requires rapid trophoblast proliferation, which is activated by the renin angiotensin system (RAS). In the first trimester, when placental growth is maximal, the mRNA expression of placental prorenin (REN), angiotensinogen (AGT) and the type 1 angiotensin receptor (AGTR1) is highest. We have shown that expression of several miRNAs (miR-378, miR-181a-3p (targeting both REN and ACE), miR-663, miR-181a-5p (targeting REN), miR-892 (targeting AGT) and miR-483 (targeting ACE, AGT and AGTR1), are reduced in first trimester human placenta. We propose that they play a role in post-transcriptional regulation of the placental RAS. Shallow placentation may result from altered expression of these miRNAs, and therefore altered placental RAS expression, leading to pregnancy complications. In this study we examined the effects of these miRNAs on the expression of their predicted placental RAS targets, and on the ability of trophoblasts to proliferate.

The effects of miRNA mimics for the chosen miRNAs on RAS mRNA abundances were measured. In another series of experiments, HTR-8/SVneo cells were cultured in an xCELLigence real-time cell-analysis system for 24h to establish a baseline cell index (measured by electrical impendence). After 24h, varying concentrations of miRNA mimics (that mimic the activity of a specific endogenous miRNAs) were added and their effect on trophoblast proliferation measured. The rate of cell proliferation was calculated as the rate of change in cell index (slope).

miRNA mimics for miR-378, miR-181a-3p, miR-663, miR-483 and miR-181a-5p significantly reduced the ability of trophoblast cells to proliferate. The miR-892 mimic had a biphasic effect on trophoblast proliferation, with low concentrations increasing proliferation and high concentrations decreasing proliferation. In cells treated with miR-181a-5p mimic, downregulation of REN mRNA was observed. Further experiments are ongoing.

Overall, this suggests that if these miRNAs are upregulated early in placentation they could repress RAS activity, decreasing trophoblast proliferation and reducing placental growth.