Regulation of the human placental (pro)renin receptor-prorenin-angiotensin system by microRNAs

• Published in: Molecular human reproduction 2018-09, Vol.24 (9), p.453-464
• Main Authors: Wang, Yu, Lumbers, Eugenie R, Arthurs, Anya L, Corbisier de Meaultsart, Celine, Mathe, Andrea, Avery-Kiejda, Kelly A, Roberts, Claire T, Pipkin, Fiona Broughton, Marques, Francine Z, Morris, Brian J, Pringle, Kirsty G
• Format: Article
• Language: English
• Subjects: Angiotensinogen - genetics; Angiotensinogen - metabolism; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Female; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; Placenta - metabolism; Pre-Eclampsia - genetics; Pre-Eclampsia - metabolism; Pregnancy; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Renin-Angiotensin System - genetics; Renin-Angiotensin System - physiology; Trophoblasts - metabolism
• ISSN: 1460-2407; 1460-2407
• DOI: 10.1093/molehr/gay031

Are any microRNAs (miRNAs) that target the placental renin-angiotensin system (RAS) in the human placenta suppressed in early gestation? Overall, 21 miRNAs with predicted RAS mRNA targets were less abundant in early versus term placentae and nine were more highly expressed. Regulation of human placental RAS expression could alter placental development and therefore normal pregnancy outcome. The expression of genes encoding prorenin (REN), angiotensinogen, (pro)renin receptor, angiotensin converting enzyme 2, and the angiotensin II type 1 receptor are highest in early gestation, at a time when oxygen tension is at its lowest. Studies have shown that the human placental RAS is sensitive to oxygen, as are some miRNAs that regulate RAS mRNAs. We propose that in early pregnancy, the prevailing low O2 tension, by suppression of levels of miRNAs that target RAS mRNAs, results in increased expression of RAS mRNAs and encoded proteins. As gestation proceeds and the prevailing oxygen tension rises, abundance of these miRNAs increases, and placental RAS mRNA expression is suppressed. The expression of miRNAs was compared in human placentae collected in early (10-11 weeks; n = 7) and mid-gestation (14-18 weeks; n = 8) with placenta collected at term (38-40 weeks; n = 8). Expression of placental miRNAs in women with early (29-35.1 weeks; n = 8) or late-onset pre-eclampsia (PE) (>34-weeks gestation; n = 8) and gestational age matched preterm (31.6-35.1 weeks; n = 8) and term normotensive controls were also compared. Agilent Human miRNA microarray v19 was used to detect up to 2006 miRNAs in four placentae from each group. Statistically different levels of expression were determined and refined using predictive modelling. Placental miRNAs predicted to target RAS mRNAs were identified in three databases. Differences detected on the array were confirmed for some miRNAs by semi-quantitative RT-PCR (qPCR, n = 7-8 for all groups). Two differentially expressed miRNAs that were known to target human renal REN mRNA (miR-181a-5p and miR-663) were transfected into human HTR-8/SVneo trophoblast cells to examine their effect on placental REN expression and prorenin levels. In early gestation placentae, 186 miRNAs were differentially expressed compared with term placentae (109 increased, 77 decreased). Thirty of the differentially expressed miRNAs were predicted to target RAS components. In mid-gestation placentae, 117 miRNAs were differentially expressed compared with term placentae