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-κB (NF-κB) activation.

Methods and 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-κB activation in VSMC and trophoblasts. AT₁-AA activated NF-κB. Inhibitor-κBα (I-κBα) 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-κB activation. VSMC from p47phox−/− mice showed markedly reduced ROS generation and NF-κB 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-κB was activated and I-κBα reduced in placentas from preeclamptic women.

Conclusions— NADPH oxidase is potentially an important source of ROS that may upregulate NF-κB in preeclampsia. We suggest that AT₁-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.