Angiotensin Receptor Agonistic Autoantibody-Mediated Soluble Fms-Like Tyrosine Kinase-1 Induction Contributes to Impaired Adrenal Vasculature and Decreased Aldosterone Production in Preeclampsia

Abstract

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy associated with decreased circulating aldosterone levels. However, the molecular mechanisms underlying aldosterone reduction in PE remain unidentified. Here we demonstrate that reduced circulating aldosterone levels in the preeclamptic women are associated with the presence of angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) and elevated soluble Fms-like tyrosine kinase-1 (sFlt-1), two prominent pathogenic factors in PE. Using an adoptive transfer animal model of PE, we provide in vivo evidence that the injection of IgG from women with PE, but not IgG from normotensive individuals, resulted in hypertension, proteinuria and a reduction in aldosterone production from 1377±272 pg/ml to 544±92 pg/ml (P<0.05) in pregnant mice. These features were prevented by co-injection with an epitope peptide that blocks antibody-mediated AT1 receptor (AT1R) activation. In contrast, injection of IgG from preeclamptic women into non-pregnant mice induced aldosterone levels from 213±24 pg/ml to 615±48 pg/ml (P<0.05). These results indicate that maternal circulating autoantibody in preeclamptic women is a detrimental factor causing decreased aldosterone production via AT1R activation in a pregnancy-dependent manner. Next, we found that circulating sFlt-1 was only induced in autoantibody-injected pregnant mice but not non-pregnant mice. As such, we further observed vascular impairment in adrenal glands of pregnant mice. Finally, we demonstrated that infusion of VEGF121 attenuated autoantibody-induced adrenal gland vascular impairment resulting in a recovery in circulating aldosterone (from 544±92 to 1110±269 pg/ml, P<0.05). Overall, we revealed that AT1-AA-induced sFlt-1 elevation is a novel pathogenic mechanism underlying decreased aldosterone production in PE.

Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia

“…6a). Consistent with earlier in-vivo animal studies [11], the short-term presence (24 h) of AT 1 -AA at a low level (0.5 mg/ml) stimulated both cellular ALD secretion and cell growth (Fig. 6a and Fig.…”

“…Recently, some interesting findings support a model in which AT 1 -AA-mediated sFlt-1 elevation accounts for a reduction of ALD production by impairing adrenal gland vasculature in the pregnant mice with hypertension and proteinuria [11]. However, effects of AT 1 -AA on ALD production, independent of pregnancy, especially in terms of the impact of long-term circulation of AT 1 -AA, were not examined in the study, and the correlation of AT 1 -AA to ALD in preeclampsia patients remains unknown.…”

“…It has been well documented that AT 1 -AA increases sFlt-1 in pregnant mice, which blocks vascular endothelial growth factor (VEGF)-mediated signaling that is important for normal endothelial function and thereby results in hypertension and renal dysfunction [4,23]. Notably, Siddiqui et al [11] reported that AT 1 -AA-mediated excessive sFlt-1 levels were also responsible for the adrenal gland vascular impairment and consequent ALD reduction in a pregnancy-dependent manner, which were attenuated by injection of VEGF 121 into pregnant mice. Data from our clinical study complement these animal studies, showing an inverse correlation between AT 1 -AA and ALD in women with early-onset preeclampsia, accompanied by high proteinuria.…”

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

“…Volume expansion prevails in pregnancy, while tight control by the renin‐angiotensin system (RAS) and consecutive aldosterone production via tubular Na + sensing1 is uncoupled in pregnancy 2, 3, 4. In pregnancy, aldosterone levels are high despite plasma volume expansion and also less responsive to increased Na + intake.…”

Syntheses of Two Co(II) and Ni(II) Complexes with 2-(1H-Imidazolyl-1- methyl)-1H-benzimidazole and 1,4-Benzenedicarboxylate Ligands and Their Effect on Cardiac Fibroblasts Proliferation

“…Being a major pathogenic factor, AngII can induce cardiac fibroblasts proliferation, increase collagen synthesis, produce myocardial fibrosis, and play a very important role in the activation and the development of various cardiovascular diseases, such as chronic heart failure, myocardial infarction, arrhythmia and others [37]. Many studies have confirmed that many drugs can protect myocardium through inhibition of the biological effect of AngII.…”