| Background:Preeclampsia(PE)is a syndrome,not just an organogenic disorder,and is a leading cause of maternal and fetal morbidity and mortality worldwide.The only current treatment modality is termination of pregnancy,so the exploration of safe and effective preventive and therapeutic drugs is an important way.Metformin is expanding its therapeutic role as a new use of an old drug.In vitro studies have shown that metformin stimulates angiogenesis,protects endothelial cells,is anti-inflammatory and inhibits oxidative stress,and resists trophoblastic risk factors,thus having a preventive and curative effect on preeclampsia.In this study,we aimed to investigate the effects of metformin on the expression of placental endoplasmic reticulum stress factors glucose regulated protein 78(GRP78)and cysteine aspartic acid specific protease 12(caspase12)in preeclamptic rats and explore the possible mechanism of action.Objective:To detect the effects of metformin on the expression of GRP78 and caspase12,placental endoplasmic reticulum stress factors,and to investigate the possible mechanisms of metformin action in preeclamptic rats.Methods:Thirty successfully conceived SD rats were randomly divided into 3 groups: control(Control),model(Model)and metformin(Metformin)groups,10 rats in each group.To construct the pre-eclampsia rat model,we used L-nitroso-arginine methyl ester(L-NAME)as an inducer.The model and metformin groups were induced to develop preeclampsia by subcutaneous injection of L-NAME 200 mg/kg/d from GD 14 to 18,and the control group was injected with an equal amount of saline subcutaneously at the same days of pregnancy;from GD 14 to 18,the metformin group received 200 mg/kg/d metformin gavage daily;the model group was treated with an equal dose of saline at the corresponding days of pregnancy Gavage.Blood pressure was measured on GD0,12,15 and 19 by a non-invasive blood pressure measurement system in rats,and 24-h urine was collected in metabolic cages on GD12 and 19 and measured for urinary protein.The placenta was dissected and removed at GD20,and the body weight,crown-rump length and placental diameter and weight were recorded.q PCR was used to detect the mRNA levels of GRP78 and caspase12 in placental tissues.Western blot was used to detect the protein levels of GRP78 and caspase12 in placental tissues.TUNEL method was used to detect apoptosis in placental tissues.Results:1.There was no statistical difference in systolic blood pressure levels in GD0 and GD12 in the three groups;compared with the control group,systolic blood pressure levels in GD15 and GD19 in the model group were increased(P<0.01);compared with the model group,systolic blood pressure levels in GD15 and GD19 in the metformin group were decreased(P<0.01).2.In GD12,24-hour urinary protein was not significantly different in the three groups of rats;compared with the control group,24-hour urinary protein was significantly elevated in the model group in GD19(P<0.01);compared with the model group,24-hour urinary protein was not significantly elevated after metformin intervention(P<0.01).3.Compared with the fetal rats in the control group,the fetal rats in the model group had decreased body weight(P<0.05)and shorter crown-rump length(P<0.01);compared with the fetal rats in the model rats,the fetal rats in the metformin group had elevated body weight and crown-rump length near normal levels(P<0.05).In contrast,there was no statistical difference in placental weight and diameter between the groups.4.The mRNA and protein levels of GRP78 and caspase12 were significantly increased in the model group compared with the control group(P<0.01);the mRNA and protein levels of GRP78 and caspase12 were significantly decreased in the metformin intervention group compared with the model group(P<0.01).5.The TUNEL results showed that the apoptosis of rat placental tissue was significantly increased in the model group compared with the control group,and the metformin group showed significant improvement in placental tissue apoptosis after the intervention.Conclusion:Metformin had a protective effect on preeclamptic rats,improved symptoms and adverse pregnancy outcome in preeclamptic rats,and reduced the expression levels of endoplasmic reticulum stress factor GRP78 and caspase12 in placental tissues of preeclamptic rats,and the mechanism may be related to the inhibition of endoplasmic reticulum stress-induced apoptosis. |
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