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The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage.Our findings highlight AT(1)-AAs as important therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

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Human IgG crosses the mouse placenta and can be detected in fetal mouse sera where it retains biological activity. (A–C) Human IgG could be detected in fetal mouse circulation by Western blotting (A) and ELISA (B). IgGs from normotensive or preeclamptic pregnant women were injected into pregnant mice at E13 and E14. Fetal sera were collected upon sacrifice on E18. Human IgG was detected in fetal mouse circulation (born to dams injected with human IgG) by Western blotting (A) using an anti–human IgG antibody, but not in the circulation of mice born to dams without human IgG injection. The concentration of human IgG in fetal mouse circulation was detected by an ELISA specific for human IgG (B). IgGs from both normotensive and preeclamptic pregnancies were detectable in fetal mice circulation, and the level of IgGs in fetal circulation between the two injected groups (n = 7 for each group in three independent experiments) was not significantly different (P > 0.05). However, the only group whose serum harbored antibodies that recognized the AT1 receptor and maintained the biological activity was the fetuses of preeclamptic IgG-injected mice (C). This was assessed by using a bioassay wherein AT1 receptor activation induces luciferase activity in transfected CHO-NFAT cells (n = 5 for each variable in two independent experiments). Data are expressed as means ± SEM. *, P < 0.01 versus normotensive IgG treatment; **, P < 0.01 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
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fig2: Human IgG crosses the mouse placenta and can be detected in fetal mouse sera where it retains biological activity. (A–C) Human IgG could be detected in fetal mouse circulation by Western blotting (A) and ELISA (B). IgGs from normotensive or preeclamptic pregnant women were injected into pregnant mice at E13 and E14. Fetal sera were collected upon sacrifice on E18. Human IgG was detected in fetal mouse circulation (born to dams injected with human IgG) by Western blotting (A) using an anti–human IgG antibody, but not in the circulation of mice born to dams without human IgG injection. The concentration of human IgG in fetal mouse circulation was detected by an ELISA specific for human IgG (B). IgGs from both normotensive and preeclamptic pregnancies were detectable in fetal mice circulation, and the level of IgGs in fetal circulation between the two injected groups (n = 7 for each group in three independent experiments) was not significantly different (P > 0.05). However, the only group whose serum harbored antibodies that recognized the AT1 receptor and maintained the biological activity was the fetuses of preeclamptic IgG-injected mice (C). This was assessed by using a bioassay wherein AT1 receptor activation induces luciferase activity in transfected CHO-NFAT cells (n = 5 for each variable in two independent experiments). Data are expressed as means ± SEM. *, P < 0.01 versus normotensive IgG treatment; **, P < 0.01 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.

Mentions: To determine if AT1-AAs can cross the mouse placenta and enter fetal circulation, we took advantage of the autoantibody-injected model of preeclampsia. Specifically, pregnant mice were injected with total IgG from normotensive pregnant women or from women with preeclampsia on embryonic day (E) 13 and E14. Blood was obtained from the dams and their fetuses upon sacrifice on E18 and examined for the presence of human IgG using Western blotting and ELISA. The results (Fig. 2, A and B) showed that similar amounts of human IgG were present in the maternal and fetal sera of antibody-injected pregnant mice. To determine if the preeclamptic IgG retained AT1 receptor agonistic activity after crossing the mouse placenta and entering fetal circulation, human IgG isolated from mouse fetal circulation was assayed for its ability to activate AT1 receptors using a reporter cell line in which AT1 receptor activation results in the activation of an NFAT-luciferase reporter gene. The results (Fig. 2 C) showed that IgG from the fetal blood of pregnant mice injected with preeclamptic IgG retained AT1 receptor agonistic activity. However, the fetuses of dams injected with IgG derived from normotensive patients harbored IgG that could not stimulate luciferase activity (Fig. 2 C). These data indicate that human AT1-AAs from women with preeclampsia cross the mouse placenta and enter fetal mouse circulation, where they retain the ability to activate AT1 receptors.


The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

Human IgG crosses the mouse placenta and can be detected in fetal mouse sera where it retains biological activity. (A–C) Human IgG could be detected in fetal mouse circulation by Western blotting (A) and ELISA (B). IgGs from normotensive or preeclamptic pregnant women were injected into pregnant mice at E13 and E14. Fetal sera were collected upon sacrifice on E18. Human IgG was detected in fetal mouse circulation (born to dams injected with human IgG) by Western blotting (A) using an anti–human IgG antibody, but not in the circulation of mice born to dams without human IgG injection. The concentration of human IgG in fetal mouse circulation was detected by an ELISA specific for human IgG (B). IgGs from both normotensive and preeclamptic pregnancies were detectable in fetal mice circulation, and the level of IgGs in fetal circulation between the two injected groups (n = 7 for each group in three independent experiments) was not significantly different (P > 0.05). However, the only group whose serum harbored antibodies that recognized the AT1 receptor and maintained the biological activity was the fetuses of preeclamptic IgG-injected mice (C). This was assessed by using a bioassay wherein AT1 receptor activation induces luciferase activity in transfected CHO-NFAT cells (n = 5 for each variable in two independent experiments). Data are expressed as means ± SEM. *, P < 0.01 versus normotensive IgG treatment; **, P < 0.01 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
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fig2: Human IgG crosses the mouse placenta and can be detected in fetal mouse sera where it retains biological activity. (A–C) Human IgG could be detected in fetal mouse circulation by Western blotting (A) and ELISA (B). IgGs from normotensive or preeclamptic pregnant women were injected into pregnant mice at E13 and E14. Fetal sera were collected upon sacrifice on E18. Human IgG was detected in fetal mouse circulation (born to dams injected with human IgG) by Western blotting (A) using an anti–human IgG antibody, but not in the circulation of mice born to dams without human IgG injection. The concentration of human IgG in fetal mouse circulation was detected by an ELISA specific for human IgG (B). IgGs from both normotensive and preeclamptic pregnancies were detectable in fetal mice circulation, and the level of IgGs in fetal circulation between the two injected groups (n = 7 for each group in three independent experiments) was not significantly different (P > 0.05). However, the only group whose serum harbored antibodies that recognized the AT1 receptor and maintained the biological activity was the fetuses of preeclamptic IgG-injected mice (C). This was assessed by using a bioassay wherein AT1 receptor activation induces luciferase activity in transfected CHO-NFAT cells (n = 5 for each variable in two independent experiments). Data are expressed as means ± SEM. *, P < 0.01 versus normotensive IgG treatment; **, P < 0.01 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
Mentions: To determine if AT1-AAs can cross the mouse placenta and enter fetal circulation, we took advantage of the autoantibody-injected model of preeclampsia. Specifically, pregnant mice were injected with total IgG from normotensive pregnant women or from women with preeclampsia on embryonic day (E) 13 and E14. Blood was obtained from the dams and their fetuses upon sacrifice on E18 and examined for the presence of human IgG using Western blotting and ELISA. The results (Fig. 2, A and B) showed that similar amounts of human IgG were present in the maternal and fetal sera of antibody-injected pregnant mice. To determine if the preeclamptic IgG retained AT1 receptor agonistic activity after crossing the mouse placenta and entering fetal circulation, human IgG isolated from mouse fetal circulation was assayed for its ability to activate AT1 receptors using a reporter cell line in which AT1 receptor activation results in the activation of an NFAT-luciferase reporter gene. The results (Fig. 2 C) showed that IgG from the fetal blood of pregnant mice injected with preeclamptic IgG retained AT1 receptor agonistic activity. However, the fetuses of dams injected with IgG derived from normotensive patients harbored IgG that could not stimulate luciferase activity (Fig. 2 C). These data indicate that human AT1-AAs from women with preeclampsia cross the mouse placenta and enter fetal mouse circulation, where they retain the ability to activate AT1 receptors.

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage.Our findings highlight AT(1)-AAs as important therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

Show MeSH
Related in: MedlinePlus