Angiotensin II Type 1 Receptor Antibodies and Increased Angiotensin II Sensitivity in Pregnant Rats

Abstract

Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-α and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia- inducible factor 1α was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an “autoimmune-activating receptor” that could contribute to Ang II sensitivity and possible to preeclampsia.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…Circulating AT1-AA could directly agonize the AT1 receptor on the afferent arteriole and synergize with circulating AII, thereby impairing renal function (19). Furthermore, this synergy may contribute to the increase in systemic AII pressor response in PE (76,201). Although these exciting and provocative data emerging from PE animal models provide much-needed proof of concept that angiogenic growth factors, proinflammatory cytokines, and AT1 autoantibodies are indeed likely to be mediators of disease pathogenesis, the precise interaction among these various inciting agents and the chain of events leading to reduced perfusion of maternal organs, including the kidneys and hypertension in PE, require further clarification.…”

Retraction: Etiopathology of preeclampsia — Recent progress from the perspective of a poor/ischemic placenta

“…Angiotensin II is the endogenous ligand for the AT1 receptor, and thus increased activation of this receptor by autoantibodies could induce the hypertension and vascular injury observed in preeclampsia. 78) Moreover, AT1-AA stimulates sFlt-1 secretion, 79) and AT1-AA binds to endothelial and vascular cells, causing endothelial damage and vasoconstriction. …”

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

“…Ang II sensitivity has since been well described to occur prior to the clinical signs and symptoms of preeclampsia (3,6), yet the mechanism remains unknown, thereby preventing therapeutic intervention. Several hypotheses have been proposed, including agonistic autoantibodies to the Ang II type 1 receptor (AT1R) (7,8), AT1R and bradykinin B 2 heterodimerization (9, 10), regulation of G protein signaling (11), and activation of uteroplacental renin-angiotensin system (RAS) (12,13). These postulates have yielded critical pathophysiological data; however, as yet no mechanism for the generalized sensitivity to vasopressors in preeclampsia has been elucidated.…”