Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation.
BACKGROUND
Preeclampsia is a serious disorder of pregnancy characterized by hypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in platelets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associated with preeclampsia.


RESULTS
We tested the hypothesis that AT1 receptor-agonistic antibodies (AT1-AAs) could activate AT1 receptors, leading to an increased intracellular concentration of free calcium and to downstream activation of Ca2+ signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca2+ mobilization. IgG from all preeclamptic patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+ by AT1-AAs was blocked by losartan, an AT1 receptor antagonist, and by a 7-amino-acid peptide that corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1-AA-stimulated mobilization of intracellular Ca2+ results in the activation of the transcription factor, nuclear factor of activated T cells.


CONCLUSIONS
These results suggest that maternal antibodies capable of activating AT1 receptors are likely to account for increased intracellular free Ca2+ concentrations and changes in gene expression associated with preeclampsia.
Thway
Theingi M
TM
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Shlykov
Sergiy G
SG
Day
Mary-Clare
MC
Sanborn
Barbara M
BM
Gilstrap
Larry C
LC
Xia
Yang
Y
Kellems
Rodney E
RE
D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology; D016466:CHO Cells / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D011225:Pre-Eclampsia / Q000276:immunology*; D011247:Pregnancy; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D001323:Autoantibodies; D001324:Autoantigens; D004268:DNA-Binding Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D014157:Transcription Factors; D049410:Luciferases, Renilla