Abstract 066: Decoy Peptide Attenuates The Syndrome Of preeclampsia In A Rodent Model
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Background: Preeclampsia (preE) is a serious complication of pregnancy manifested by high blood pressure, proteinuria, and edema. In a previous study, we demonstrated that circulating levels of soluble (pro)renin receptor ((P)RR) were elevated at delivery in patients with preE, and that both plasma and placental (pro)renin were elevated in preE patients and in a rat model of preE. Decapeptide based on this handle-region sequence (handle-region peptides or HRP) can block binding of (pro)renin to (P)RR. Objective: The goal of this study is to develop and characterize HRP as an innovative treatment for preE. Methods and Materials: The human extravillous cytotrophoblast (CTB) cell line Sw-71 used in these studies was derived from first trimester chorionic villous tissue. (P)RR (2 nM) was incubated in 1.0 mL medium with the receptor-expressing CTB cells for 0, 6, 12, 18, or 24 hours, followed by renin activity assay to determine the percent binding and activation of (P)RR. Female Sprague-Dawley rats (200-250 g, first-time pregnant with confirmation by vaginal plug, Harlan) are randomly assigned to three groups (n=8 per group): 1) NP: normal pregnant rats; 2) PDS: pregnant animals injected initially with 12.5 mg of DOCA in a depot form intraperitoneally, followed by a weekly injection of 6.5 mg, and whose drinking water was replaced with 0.9% saline; 3) PDS-HRP: rats administered DOCA and saline as for Group 2, and also given HRP (10 mg/kg, i.p.) daily from day 10 through day 20 of pregnancy. Results: (Pro)renin was non-proteolytically activated by binding to (P)RR on the cell membrane of CTB cells, while HRP inhibited binding and attenuated activation of (P)RR. The HRP decoy peptide normalizes blood pressure, proteinuria, and birth numbers in DOCA model of preE. When HRP was administered following the onset of hypertension, the BP, proteinuria, and number of pups were normalized to control normal pregnancy. Conclusions: HRP inhibits the binding of (pro)renin to (P)RR. This study in animal model of preE suggests HRP blockade of (P)RR can attenuate the disease. (P)RR and (pro)renin levels are elevated in preE patients and in their placenta, as well as in a rat model of preE. This data suggests HRP as a potential therapeutic for intervention of RAS signaling in preE.
