Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

Abstract

Abstract-We used rats transgenic for the human angiotensinogen (hAogen) gene and the human renin (hRen) gene and crossed the strains to produce a model of preeclampsia in the dams. The female (nϭ9) hAogen ϫ male hRen cross had severe (telemetry-measured) hypertension and albuminuria, which developed during the last trimester of pregnancy and subsided after delivery. The converse cross (nϭ9) and control (nϭ9) SD rats did not. We demonstrated that the female hAogen ϫ male hRen cross had agonistic antibodies capable of activating the angiotensin (Ang) II AT1 receptor (AT1R-AA) and defined the epitope on the receptor's second extracellular loop. The phenomenon also occurs in humans with preeclampsia. The rats displayed renal histology reminiscent of preeclampsia, including fibrin deposition confined to the glomeruli. The complement system was activated in glomeruli and IgG deposits were present that may represent AT1R-AA. Finally, we observed an atherosis-like lesion in the spiral arteries of the placental bed, which we called placental-bed arteriolosclerosis. Our model may be relevant to preeclampsia in humans. Key Words: preeclampsia Ⅲ rats, transgenic Ⅲ antibodies Ⅲ immune systems Ⅲ renin-angiotensin system P reeclampsia, proteinuria, and severe hypertension in the latter part of pregnancy affects Ϸ3% of women in industrialized nations and a much higher percentage of women in underdeveloped countries. 1 In all countries, preeclampsia represents the major cause of maternal and fetal morbidity and mortality. Constructing a suitable animal model has been difficult. Takimoto et al described hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. 2 Mice were generated transgenic for the human renin (hRen) and human angiotensinogen (hAogen) genes. The rodent and human renin-angiotensinogen systems do not interact and single transgenic animals are normotensive. Severe hypertension develops in double-transgenic offspring. The investigators observed that hypertension developed in the latter third of pregnancy in hAogen dams mated with hRen males. They showed that secreted active hRen of placental origin was capable of reacting with hAogen in the dams to produce angiotensin (Ang) II. Takimoto et al suggested that the transgenic mice might offer a unique model of "genetically induced" preeclampsia. 2 We showed that the same phenomenon exists in a rat transgenic model. 3 We used telemetric blood pressure measurements in that study to document the precise timing of the model; however, we presented no functional or histological data. 3 We have also studied preeclamptic women and found that they produce an agonistic antibody to the Ang II receptor (AT1R). 4,5 These autoantibodies (AT1-AA) activate the receptor. The activation sets into motion a chain of signaling events that could be responsible for the clinical disease. 6 We have now restudied our transgenic animal model and have observed that the rats also have these novel autoantibodies. MethodsSprague-Dawley (SD) rats harboring the human Aogen...

Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature

“…15 Thus, the antibody in combination with Ն1 other factors could still be a relevant pathogenetic factor for pregnancy pathology, as also indicated by recent findings of Dechend et al in transgenic rats. 8 Our study has 2 major implications. The clinical importance of the AT 1 -AA has changed in the light of evidence characterizing it as an early but not entirely specific marker for preeclampsia.…”

“…The fact that the AT 1 -AA is an interesting candidate for mediating or even causing the disease was further supported by the finding that a transgenic rat model of preeclampsia is also characterized by the presence of the AT 1 -AA. 8 However, decisive evidence that the detected autoantibody is causative for preeclampsia has not yet been provided. Attention was focused on determining whether AT 1 -AA precedes the clinical symptoms of preeclampsia or is only a secondary effect of clinically evident preeclampsia and therefore not the primary cause of the disease.…”

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

“…Dechend and colleagues 64 used the cardiomyocyte contraction assay to detect the presence of AT1 agonistic antibody in pregnant transgenic rats overexpressing components of the human renin angiotensin system. Peptide competition experiments showed that the antibody interacted with the same 7-aa epitope on the second extracellular loop of the AT1 receptor defined by AT1-AA obtained from women with preeclampsia.…”

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

“…19 The dams expressing human angiotensinogen develop hypertension and proteinuria during pregnancy after mating with males expressing the human renin. 18 The offspring are growth restricted, 20 comparable to what is observed in spontaneously occurring, early-onset preeclampsia in pregnant women. The model exhibits pathological endovascular trophoblast cell invasion with altered uteroplacental vascular remodeling.…”

“…Because shallow endovascular trophoblast cell invasion is considered to be causal for the pathological event initiating preeclampsia symptoms and signs, 17 we hypothesized that depletion or reduction of NK cells associated with increased trophoblast cell invasion ameliorates the preeclamptic phenotype in our rat model. We worked with our double-transgenic rat preeclamptic model where the preeclamptic phenotype has been established in rats 18 and mice. 19 The dams expressing human angiotensinogen develop hypertension and proteinuria during pregnancy after mating with males expressing the human renin.…”