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Abstract
Many circumstantial evidences from human and animal studies suggest that complement cascade dysregulation may play an important role in pregnancy associated complications including preeclampsia. Deletion of rodent specific complement inhibitor gene, Complement Receptor 1-related Gene/Protein y (Crry) produces embryonic lethal phenotype due to complement activation. It is not clear if decreased expression of Crry during pregnancy produces hypertensive phenotype. We downregulated Crry in placenta by injecting inducible lentivialshRNA vectors into uterine horn of pregnant C57BL/6 mice at the time of blastocyst hatching. Placenta specific downregulation of Crry without significant loss of embryos was achieved upon induction of shRNA using an optimal doxycycline dose at mid gestation. Crry downregulation resulted in placental complement deposition. Late-gestation measurements showed that fetal weights were reduced and blood pressure increased in pregnant mice upon downregulation of Crry suggesting a critical role for Crry in fetal growth and blood pressure regulation.
Highlights
Complement cascade consisting of more than 30 proteins is a part of innate immune system
A doxycycline dose of 75 μg/mL resulted in downregulation of Complement Receptor 1-related Gene/Protein y (Crry) with minimal embryo loss in CrryshRNA injected mice and this dose was used in the subsequent experiments
The ELISA results showed that serum C3 levels were not different between the two groups (Fig 4D). These results suggested that liver C3 transcript levels were increased upon placental complement activation in CrryshRNA mice, and C3 protein levels were not higher corresponding to mRNA levels in CrryshRNA group indicating secretion of excess C3 into circulation
Summary
Complement cascade consisting of more than 30 proteins is a part of innate immune system. All three pathways converge at the level of C3 activation and proceed to form a common cellulolytic pore like structure, membrane attack complex (MAC) in cell membrane [2]. Both in humans and mice, self-cells are protected from complement attack by three membrane-bound proteins, decay accelerating factor (DAF or CD55), membrane cofactor protein (MCP or CD46) and MAC inhibitory protein (CD59) [3,4,5]. In addition to DAF, MCP and CD59, complement system of rodents contains a specific inhibitor, Complement Receptor 1-related Gene/Protein y (Crry). The expression of Crry has been observed in developing murine placenta [6]
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