[169-POS] : Elevated C-reactive protein contributes to preeclampsia via kinin signaling pathways.

OBJECTIVES: Despite intensive research, the pathogenesis of PE remains a mystery. Our study demonstrates a novel interaction between C-reactive protein (CRP) and Neurokinin B (NKB) leading to enhanced activation of the Neurokinin 3 receptor (NK3R).

METHODS: Patient sera and placental tissue were obtained from Memorial Hermann Hospital, Houston, TX. CRP and NKB levels were quantified by ELISA and western blot in term sera and placentas. Coimmunofluorescence was used to colocalize CRP and NKB in placental trophoblast cells. To model PE, pregnant C57BL/6 mice were injected with CRP or with a NK3R antagonist, SB222200, on E13/14. Blood pressure was monitored via tail cuff. Proteinuria was measured via metabolic cage and ELISA on E17. Further verification of the role of the kinin system was undertaken by an in vivo siRNA knockdown of the NK3R and an enzyme involved in phosphocholination of NKB, PCYT1b.

RESULTS: CRP, an acute phase reactant, was elevated 13-fold in sera and 2-fold in placentas of PE patients. To determine the role of elevated CRP in PE, we injected CRP into pregnant mice. Injection of CRP induced hypertension and proteinuria, indicating its direct role in PE. CRP is known to bind to phosphocholine on damaged cell membranes. NKB, a placentally-enriched peptide and PE-related pathogenic molecule, has been shown to be phosphocholinated, increasing its stability and enhancing NK3R activation. CRP and NKB were found to co-localize to the membrane of human placental trophoblast cells in terminal villi. Finally, in vivo evidence showed nanoparticle-encapsulated siRNA knockdown of NK3R and PCYT1b, and pharmacologic antagonism of NK3R significantly reduced CRP-induced hypertension (159.5 mmHg mean systolic CRP vs. ⩽139 mmHg CRP + treatment groups) and proteinuria in pregnant mice.

CONCLUSIONS: Our findings demonstrate that elevated CRP and NKB/NK3R signaling contribute to disease development. These findings reveal novel therapeutic targets and pathogenic biomarkers for PE.

DISCLOSURES: N. Parchim: None. W. Wang: None. T. Iriyama: None. O.A. Ashimi: None. C. Liu: None. A.H. Siddiqui: None. S. Blackwell: None. B. Sibai: None. R.E. Kellems: None. Y. Xia: None.