Objective:To investigate the effect of metformin(MET)on endoplasmic reticulum stress-induced apoptosis and its role and molecular mechanisms in preeclamptic(PE)rats.Methods:Thirty SD rats were ran-domly assigned into control,PE and MET groups,10 in each group.From days 14 to 18 of gestation,rats in the PE and MET groups were subcutaneously injected with L-nitro-arginine methyl ester(L-NAME)at a dose of 200 mg/(kg·d),while the control group was administered subcutaneous injections containing a 0.9％solution of sodium chloride at the same dose.Additionally,the MET group was administered MET by gavage at a dose of 200 mg/(kg·d)from days 13 to 18 of gestation.On days0,6,12,15,17,and 19 of pregnancy,blood pressure of rats was measured.On days 12 and 19 of pregnancy,24-hour urinary protein content was assessed.On day 20 of pregnan-cy,rats were anesthetized and underwent cesarean section to measure pup weight,crown-rump length,placental weight,and diameter.We used reverse transcription quantitative polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry(IHC)to detected mRNA and protein expression of apoptosis-related genes in rat placental tissue,and enzyme-linked immunosorbent assay(ELISA)to assess the expression of apopto-sis-related genes in rat serum.Results:Compared with the control group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuria level on day 19 of gestation were significantly higher,and body mass and top rump length of littermates were lower in the PE group,and the differences were statistically significant(P＜0.05);Compared with the PE group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuri-a level on day 19 of gestation were significantly decreased,and body mass and top rump length of littermates were increased in the MET group,and the differences were all statistically significant(P＜0.05).Pairwise com-parisons of placental weight,placental diameter,and the number of pups born among the three groups showed no statistically significant differences(P＞0.05).Compared to the control group,the PE group exhibited significantly increased expression of B-cell lymphoma-2(Bcl-2)associated X protein(Bax),bcl-2 antagonist/killer 1(Bak),and apoptosis-inducing factor(AIF)mRNA and protein in placental tissues,decreased expression of Bcl-2 mRNA and protein,as well as elevated levels of Bax,Bak,and AIF in serum,while Bcl-2 expression levels were de-creased.These differences were statistically significant(P＜0.05).Compared to the PE group,the MET group exhibited decreased expression of Bax,Bak,and AIF mRNA and protein in placental tissue,along with increased expression of Bcl-2 mRNA and protein.Serum levels of Bax,Bak,and AIF were decreased,while Bcl-2 expression levels were increased.All differences were statistically significant(P＜0.05).Conclusions:L-NAME significantly induced elevated levels of apoptosis in rat placental tissues,whereas MET was able to effectively inhibit L-NAME-induced apoptosis induced by endoplasmic reticulum stress,which has the potential to be a new therapeu-tic intervention point for PE.

Objective:To investigate the effect of metformin(MET)on endoplasmic reticulum stress-induced apoptosis and its role and molecular mechanisms in preeclamptic(PE)rats.Methods:Thirty SD rats were ran-domly assigned into control,PE and MET groups,10 in each group.From days 14 to 18 of gestation,rats in the PE and MET groups were subcutaneously injected with L-nitro-arginine methyl ester(L-NAME)at a dose of 200 mg/(kg·d),while the control group was administered subcutaneous injections containing a 0.9％solution of sodium chloride at the same dose.Additionally,the MET group was administered MET by gavage at a dose of 200 mg/(kg·d)from days 13 to 18 of gestation.On days0,6,12,15,17,and 19 of pregnancy,blood pressure of rats was measured.On days 12 and 19 of pregnancy,24-hour urinary protein content was assessed.On day 20 of pregnan-cy,rats were anesthetized and underwent cesarean section to measure pup weight,crown-rump length,placental weight,and diameter.We used reverse transcription quantitative polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry(IHC)to detected mRNA and protein expression of apoptosis-related genes in rat placental tissue,and enzyme-linked immunosorbent assay(ELISA)to assess the expression of apopto-sis-related genes in rat serum.Results:Compared with the control group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuria level on day 19 of gestation were significantly higher,and body mass and top rump length of littermates were lower in the PE group,and the differences were statistically significant(P＜0.05);Compared with the PE group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuri-a level on day 19 of gestation were significantly decreased,and body mass and top rump length of littermates were increased in the MET group,and the differences were all statistically significant(P＜0.05).Pairwise com-parisons of placental weight,placental diameter,and the number of pups born among the three groups showed no statistically significant differences(P＞0.05).Compared to the control group,the PE group exhibited significantly increased expression of B-cell lymphoma-2(Bcl-2)associated X protein(Bax),bcl-2 antagonist/killer 1(Bak),and apoptosis-inducing factor(AIF)mRNA and protein in placental tissues,decreased expression of Bcl-2 mRNA and protein,as well as elevated levels of Bax,Bak,and AIF in serum,while Bcl-2 expression levels were de-creased.These differences were statistically significant(P＜0.05).Compared to the PE group,the MET group exhibited decreased expression of Bax,Bak,and AIF mRNA and protein in placental tissue,along with increased expression of Bcl-2 mRNA and protein.Serum levels of Bax,Bak,and AIF were decreased,while Bcl-2 expression levels were increased.All differences were statistically significant(P＜0.05).Conclusions:L-NAME significantly induced elevated levels of apoptosis in rat placental tissues,whereas MET was able to effectively inhibit L-NAME-induced apoptosis induced by endoplasmic reticulum stress,which has the potential to be a new therapeu-tic intervention point for PE.