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Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice

Abstract

Pre-eclampsia affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world1,2. The clinical hallmarks of this maternal disorder include hypertension, proteinuria, endothelial dysfunction and placental defects. Advanced-stage clinical symptoms include cerebral hemorrhage, renal failure and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. An effective treatment of pre-eclampsia is unavailable owing to the poor understanding of the pathogenesis of the disease. Numerous recent studies3,4,5 have shown that women with pre-eclampsia possess autoantibodies, termed AT1-AAs, that bind and activate the angiotensin II receptor type 1a (AT1 receptor). We show here that key features of pre-eclampsia, including hypertension, proteinuria, glomerular endotheliosis (a classical renal lesion of pre-eclampsia), placental abnormalities and small fetus size appeared in pregnant mice after injection with either total IgG or affinity-purified AT1-AAs from women with pre-eclampsia. These features were prevented by co-injection with losartan, an AT1 receptor antagonist, or by an antibody neutralizing seven–amino-acid epitope peptide. Thus, our studies indicate that pre-eclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from autoantibody-induced angiotensin receptor activation. This hypothesis has obvious implications regarding pre-eclampsia screening, diagnosis and therapy.

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Figure 1: Injection of IgG from women with pre-eclampsia into pregnant mice leads to hypertension and proteinuria.
Figure 2: Affinity-purified AT1-AAs induced an increase in blood pressure and proteinuria in pregnant mice.
Figure 3: Kidney damage is induced in pregnant mice by injection of IgG from women with pre-eclampsia.
Figure 4: Effects of injection of IgG from women with pre-eclampsia into nonpregnant mice.

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Acknowledgements

We thank Merck for the gift of losartan. This work was supported by US National Institutes of Health grants HL076558 (to Y.X.) and HD34130, March of Dimes grant 6-FY06-323 and the Texas Higher Education Coordinating Board (to R.E.K.).

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Authors and Affiliations

Authors

Contributions

C.C.Z. performed total IgG purification; blood pressure, urinary protein, sFlt1 and sEng measurements in antibody-injected pregnant mice; fetal kidney and placenta isolation and cell culture bioassays for AT1-AA biological activity; and contributed to writing, editing and generation of figures. Y.Z. carried out antibody injections, affinity purification and characterization of AT1-AAs, western blot experiments and ELISA for human IgG; and contributed to writing and generation of figures. R.A.I. procured human subjects' approvals, maintained the database of de-identified human subject information, measured blood pressure and urinary protein in antibody-injected nonpregnant mice, performed kidney and placental histology and contributed to writing and generation of figures. H.Z. provided expertise in kidney and placental histology and contributed to writing and editing of histological studies in both placenta and kidney. T.M. injected mice with antibody and helped with blood pressure and other measurements. E.J.P. provided expertise regarding the electron microscopic analysis of kidney. M.J.H. provided expertise in placental histology. S.M.R. provided expertise in pre-eclampsia, collected human subject samples amd analyzed human subject data. R.E.K. provided expertise in pre-eclampsia and the renin angiotensin system and contributed to the writing and editing of the manuscript. Y.X. was the principal investigator of the study, oversaw the overall design of experiments and interpretation of all results, organized the manuscript including text and figures, and did the final editing of the manuscript.

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Correspondence to Yang Xia.

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Zhou, C., Zhang, Y., Irani, R. et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 14, 855–862 (2008). https://doi.org/10.1038/nm.1856

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