AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase.
BACKGROUND
We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT1-AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT1-AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-kappaB (NF-kappaB) activation.


RESULTS
We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT1-AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT1-AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT1-AA lead to NF-kappaB activation in VSMC and trophoblasts. AT1-AA activated NF-kappaB. Inhibitor-kappaBalpha (I-kappaBalpha) expression was reduced in response to AT1-AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-kappaB activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-kappaB activation in response to Ang II and AT1-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-kappaB was activated and I-kappaBalpha reduced in placentas from preeclamptic women.


CONCLUSIONS
NADPH oxidase is potentially an important source of ROS that may upregulate NF-kappaB in preeclampsia. We suggest that AT1-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.
Dechend
Ralf
R
HELIOS Klinikum-Berlin, Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin, Germany.
Viedt
Christiane
C
Müller
Dominik N
DN
Ugele
Bernhard
B
Brandes
Ralf P
RP
Wallukat
Gerd
G
Park
Joon-Keun
JK
Janke
Jurgen
J
Barta
Peter
P
Theuer
Jurgen
J
Fiebeler
Anette
A
Homuth
Volker
V
Dietz
Rainer
R
Haller
Hermann
H
Kreuzer
Jörg
J
Luft
Friedrich C
FC
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000819:agonists / Q000276:immunology*; D014327:Trophoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D001323:Autoantibodies; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019255:NADPH Oxidases