Astragaloside IV alleviates lipopolysaccharide-induced preeclampsia-like phenotypes via suppressing the inflammatory responses

Abstract

Preeclampsia (PE) is a major cause of perinatal and maternal mortality and morbidity, which affects 2% to 8% of pregnancies in the world. The aberrant maternal inflammation and angiogenic imbalance have been demonstrated to contribute to the pathogenesis of PE. This research aimed to investigate the effect of Astragaloside IV (AsIV) in the treatment of PE and the underlying mechanisms. A rat PE-like model was established by tail vein injection of lipopolysaccharide (LPS) and different doses of AsIV (40 and 80 mg/kg) were treated at the same time. Systolic blood pressure, total urine protein and urine volume were observed. Serum and placenta inflammatory cytokines were measured by ELISA kit. The mRNA and protein expression of relative genes were analyzed by qRT-PCR and Western blotting. In PE-like rats, there were obvious increases in systolic blood pressure, total urine protein and urine volume, which were obviously alleviated by treatment with AsIV. Serum levels of interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), IL-6 and IL-18, as well as IL-4, IL-10, PIGF, VEGF and sFlt-1, were all reversed by treatment with AsIV. Meanwhile, AsIV treatment improved abnormal pregnancy outcomes, such as low litter size and low fetal weight. In addition, AsIV treatment downregulated the mRNA expression of inflammatory gene IL-1β and IL-6 in PE rats model, and AsIV treatment inhibited the activation of TLR-4, NF-κB, and sFlt-1 in the placenta of PE rats. Our findings indicated the first evidence that AsIV alleviated PE-like signs, and this improvement effect is possibly through inhibition of inflammation response via the TLR4/NF-κB signaling pathway.

Keywords: Astragaloside IV; hypertension; inflammation; preeclampsia.

FIGURE 1

Effects of AsIV on SBP, A and D; total urinary protein, B; urinary volume, C; DBP, E; MBP, F; and HR, G, in the LPS‐induced rat PE model. Data are expressed as mean ± SEM (n = 8). ^** P < .01 versus PE group, ^# P < .01 versus the PC group. AsIV, Astragaloside IV; DBP, diastolic blood pressure; HR, heart rate; LPS, lipopolysaccharide; PC, pregnant control group; PE, preeclampsia; SBP, systolic blood pressure

FIGURE 2

Effects of AsIV on serum levels of IL‐1β, A; TNF‐α, B; IL‐6, C; and IL‐18, D, in the LPS‐induced rat PE model. Data are expressed as mean ± SEM (n = 8). ^* P < .05 versus PE group, ^** P < .01 versus PE group, ^# P < .01 versus the PC group. AsIV, Astragaloside IV; IL, interleukin; LPS, lipopolysaccharide; PC, pregnant control group; PE, preeclampsia

FIGURE 3

Effects of AsIV on serum levels of IL‐4, A and IL‐10, B; and placenta levels of IL‐4, C and IL‐10, D, in the LPS‐induced rat PE model. Data are expressed as mean ± SEM (n = 8). ^* P < .05 veusus PE group, ^** P < .01 versus PE group, ^# P < .01 versus the PC group. IL, interleukin; PC, pregnant control group; PE, preeclampsia

FIGURE 4

Effects of AsIV on serum levels of PIGF, A and sFlt‐1, B; and VEGF, C and fetal weight, D, in the LPS‐induced rat PE model. Data are expressed as mean ± SEM (n = 8). ^* P < .05 versus PE group, ^** P < .01 versus PE group, ^# P < .01 versus the PC group. AsIV, Astragaloside IV; LPS, lipopolysaccharide; PC, pregnant control group; PE, preeclampsia

FIGURE 5

Effects of AsIV on mRNA expressions of IL‐1β, A; IL‐6, B; and sFlt‐1, C, in the LPS‐induced rat PE model. The representative hematoxylin and eosin (HE) staining of placenta tissue in different groups, D. Data are expressed as mean ± SEM (n = 8). ^** P < .01 versus PE group, ^# P < .01 versus the PC group. AsIV, Astragaloside IV; IL, interleukin; LPS, lipopolysaccharide; PC, pregnant control group; PE, preeclampsia

FIGURE 6

Effects of AsIV on protein expressions of TLR‐4, A; The expressions of TLR‐4, NF‐κB (nucleus), and sFlt‐1 were detected by western blotting, B; NF‐κB, C; and sFlt‐1, D, in the LPS‐induced rat PE model. Data are expressed as mean ± SEM (n = 8). ^** P < .01 versus PE group, ^# P < .01 versus the PC group. AsIV, Astragaloside IV; LPS, lipopolysaccharide; PC, pregnant control group; PE, preeclampsia