Molecular mechanism of AT₁-AA–mediated AT₁ receptor activation. Multiple signaling pathways function downstream of AT_1-AA–mediated AT₁ receptor activation. AT₁-AA–mediated AT₁ receptor activation leads to increased PKC and calcineurin activity. As a result, downstream transcription factors, such as activating protein-1, nuclear factor κB (NF-κB), and nuclear factor activating T cell (NFAT), are activated and translocate from cytosol to nucleus, leading to increased gene expression. Because AT₁ activating autoanti-bodies are bivalent IgG protein complexes, we propose that they exert their agonistic effect by cross-linking and thereby stabilizing AT₁ receptor homodimers. DAG indicates diacylglycerol; IP3, inositol triphosphate; PKC, protein kinase C.

Schematic diagrams of AT₁ receptor and the sequence of 7 amino acid antibody blocking epitope peptide. AT₁-AA interacts with second extracellular loop of AT₁ receptor. This interaction can be blocked by a specific 7 amino acid peptide.

Molecular basis of AT₁-AA production in rat models of preeclampsia: generation of AT₁-AA may be secondary to placental ischemia, vascular damage, and enhanced inflammatory response. The decreased blood flow to placenta in double transgenic rats and RUPP rats leads to placental ischemia and hypoxia. This will result in endovascular damage and the enhanced inflammatory response with increased secretion of inflammatory cytokines (eg, TNF-α). The resulting inflammatory cytokine secretion contributes to AT₁ receptor agonistic antibody production. AT₁-AA will directly induce higher blood pressure and proteinuria via AT₁ receptor activation. This may eventually lead more hypoxia, endovascular damage, and enhanced inflammatory response. Thus, we speculate that hypoxia because of reduced placental perfusion may lead to an inflammatory response that contributes to the generation of AT₁-AA. The resulting AT₁-AA may further contribute to decreased trophoblast invasion, increased hypoxia, and an enhanced inflammatory response, leading to more AT₁-AA production. Therefore, reduced placental perfusion, hypoxia, inflammatory response, and AT₁-AA production act as a detrimental cycle to contribute to pathophysiology of preeclampsia.