AT1-AA (Angiotensin II Type 1 Receptor Agonistic Autoantibody) Blockade Prevents Preeclamptic Symptoms in Placental Ischemic Rats

Abstract

Women with preeclampsia produce AT1-AA (agonistic autoantibodies to the angiotensin II type 1 receptor), which stimulate reactive oxygen species, inflammatory factors, and hypertensive mechanisms (ET [endothelin] and sFlt-1 [soluble fms-like tyrosine kinase-1]) in rodent models of preeclampsia. The placental ischemic reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits many of these features. In this study, we examined the maternal outcomes of AT1-AA inhibition ('n7AAc') in RUPP rats. Blood pressure was higher in RUPP rats versus normal pregnant (NP) rats (123±2 versus 99±2 mm Hg, <0.05), which was reduced in RUPP+'n7AAc' (105±3 versus 123±2 mm Hg, <0.05 versus RUPP). Uterine artery resistant index was increased in RUPP versus NP rats (0.71±0.02 versus 0.49±0.02, <0.05) and normalized in RUPP+'n7AAc' rats (0.55±0.03). Antiangiogenic factor sFlt-1 was elevated in RUPP versus NP rats (176±37 versus 77±15 pg/mL, <0.05) but normalized in RUPP+'n7AAc' (86±9, =0.05 versus RUPP). Plasma nitrate and nitrite were decreased (14±1 versus 20±1 µMNO, <0.05) and isoprostanes were elevated (20 117±6304 versus 2809±1375 pg/mL, <0.05) in RUPP versus NP rats; and normalized in RUPP+'n7AAc' rats; (18±2 µMNO; 4311±1 pg/mL). PPET-1 (preproendothelin-1) expression increased 4-fold in RUPP versus NP rats which were prevented with 'n7AAc'. Importantly, placental cytolytic natural killer cells were elevated in RUPP versus NP rats (8±2% versus 2±2% gated, <0.05), which was prevented in RUPP+'n7AAc' total (3±1% gated, <0.05) In conclusion, AT1-AA inhibition prevents the rise in maternal blood pressure and several pathophysiological factors associated with preeclampsia in RUPP rats and could be a potential therapy for preeclampsia.

Renal natural killer cell activation and mitochondrial oxidative stress; new mechanisms in AT1-AA mediated hypertensive pregnancy

“…Recent studies show the importance of cytolytic NK cells in PE [2,32–37]. We recently demonstrated that NK cells were increased in the RUPP rat model of PE, and that depletion of NK cells reduced circulating and placental inflammatory cytokines and improved hypertension [31,38]. Moreover, we demonstrate that NK cells are decreased in RUPP rats treated with ‘n7AAc’ [31].…”

“…In a recent study, we used a modified inhibitory peptide against the AT1-AA (‘n7AAc’), which improved blood pressure and renal function, and lowered circulating factors associated with PE, such as ET-1, sFlt-1, and isoprostanes in RUPP rats [31]. In addition, we observed an increase in NO bioavailability in RUPP rats treated with (‘n7AAc’).…”

“…In addition, we observed an increase in NO bioavailability in RUPP rats treated with (‘n7AAc’). These data suggest that the decrease in these circulating factors decreases oxidative stress, which in return increased NO bioavailability [31]. Women with preeclampsia have an increase in oxidative stress [2,4,22].…”

Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

“…Once the rat was awake and mobile, the probe recorded a standard filtration baseline rate for 15 min followed by a 5 mg/100 g BW bolus infusion of FITC-sinistrin (Frensenius Kabi Austria INC I&D) via the jugular catheter. Continuous fluorescence was measured for 2 h, and the clearance curves were calculated using MPD Lab Ver 1.0RC3 software and the one-compartment half-life ( t 1/2 ) model where t 1/2 is converted to GFR (mL/min/100 g BW) [ 25 ].…”

The role of immunity in the pathogenesis and development of pre‐eclampsia

“…Recently, a study by MARKW et al showed that the administration of a modified peptide containing seven amino acid sequences can bind with the epitope of AT1‐AA and inhibit the activation of the AT1 receptor in RUPP mice, which can improve placental ischaemia‐induced PE‐like symptoms, deceased blood pressure, and inhibit the production of anti‐angiogenic factors and vasoconstrictors. Moreover, both the pup weight and placental weight did not decrease, demonstrating that improved maternal renal function and the bioavailability of NO prevented toxicity to foetus . Therefore, blocking AT1‐AA may be an option for the better management of PE.…”