Preterm birth (PTB) is the single largest cause of death in infants and young children. 40-45% follow spontaneous labour with intact membranes and 25-30% are associated with preterm premature rupture of membranes (P-PROM). The primary cause of membrane weakness is unknown. In kidneys, the prorenin/(pro)renin receptor ((P)RR) interaction stimulates cell growth and the production of pro-fibrotic factors (including PAI-1, fibronectin and collagens), which maintains the extracellular matrix. However, the role of the prorenin/(P)RR interaction in regulating the integrity of the amnion is unknown. We postulate that prorenin, secreted by the decidua, acts upon amniotic (P)RR to stimulate pro-fibrotic factors and cell proliferation in order to maintain the amnion. With advancing gestation the prorenin/(P)RR interaction declines thus promoting membrane rupture.
Combined fetal membranes (amnion, chorion and decidua) from term and preterm non-laboring deliveries were obtained and REN (prorenin) and ATP6AP2 ((P)RR) mRNA expressions were determined by qRT-PCR. Both REN and ATP6AP2 ((P)RR) mRNA abundance was significantly decreased in term membranes compared with preterm membranes (P=0.0002 and 0.0142 respectively), which suggests that advancing gestation is associated with lower levels of expression of both REN and (P)RR. To validate the relationship between prorenin/(P)RR and membrane integrity primary amnion cells were isolated and transfected with 50 nM (P)RR siRNA. Following qRT-PCR validation for (P)RR knockdown, the effects of knockdown on downstream targets of the prorenin/(P)RR interaction and on measures of membrane integrity was determined. Inhibition of (P)RR was associated with decreased expression of Fibronectin, Collagen IV and TIMP1 mRNA; all of which play a major role in maintenance of the ECM. Thus the prorenin/(P)RR interaction is involved in maintaining amnion integrity and preventing preterm birth.