Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

The (pro)renin receptor regulates amnion matrix degradation and thus may play a role in preterm birth (#101)

Sarah J Delforce 1 2 , Eugenie R Lumbers 1 2 , Tess L Symington 1 2 , Zac Adams 1 2 , Tamas Zakar 2 3 , Kirsty G Pringle 1 2
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
  2. Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  3. School of Health and Medicine , University of Newcastle, Callaghan, NSW, Australia

Preterm birth (PTB) is the single largest cause of death in infants and young children. 25-30% are associated with preterm premature rupture of membranes (P-PROM). P-PROM is more prevalent in ‘male’ pregnancies, suggesting that the integrity of the male amnion is less than female amnion. In the kidneys, the (pro)renin receptor ((P)RR) regulates extracellular matrix production by increasing the MMP9:TIMP1 ratio. As expression of the (P)RR is higher in female amnion1, we postulated that (P)RR in amnion epithelial cells (AECs), like the kidney, regulates membrane integrity in a sex-dependent manner.

To investigate the relationship between (P)RR and membrane integrity, primary human AECs were isolated and transfected with 10 nM (P)RR or scrambled siRNA (n=8/group). Following qRT-PCR validation for (P)RR knockdown, expression of markers of membrane integrity (MMP9 and TIMP1) were determined. MMP activity was also measured using zymography. 

In female AECs, MMP9 mRNA expression (P=0.02) and metalloproteinase activity (P=0.003) was significantly lower than in male AECs. Fetal sex did not affect the expression of (P)RR or TIMP1 mRNA. (P)RR siRNA significantly reduced (P)RR mRNA expression by ~80% in both male and female AECs (both P<0.0001). (P)RR siRNA also reduced the expression of TIMP1 mRNA in both male and female AECs (P=0.006 and 0.03, respectively) but metalloproteinase activity was only enhanced in female AECs (P=0.03).

Overall, female AECs had lower levels of markers of matrix breakdown compared with male AECs. This could account for the lower prevalence of P-PROM in female pregnancies. This sex difference however does not appear to be driven by (P)RR. Inhibition of (P)RR was associated with decreased expression the membrane integrity marker (TIMP1). In female AECs there was also a rise in MMP activity. Thus, the (P)RR is likely to be involved in maintaining amnion integrity and decreased expression of (P)RR might be associated with PTB.

 

  1. Pringle KG, Conquest A, Mitchell C, Zakar T, Lumbers ER. Effects of Fetal Sex on Expression of the (Pro)renin Receptor and Genes Influenced by its Interaction With Prorenin in Human Amnion. Reprod Sci. 2015;22(6):750-757. doi:10.1177/1933719114561555