Zhou Yiyuan, Zhang Fang, Jiang Huijiao, Xu Di, Deng Dongyang
Department of Obstetrics, The First Affliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550001, P.R. China.
Exp Ther Med. 2021 Oct;22(4):1072. doi: 10.3892/etm.2021.10506. Epub 2021 Jul 28.
The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten-eleven translocation 1 (TET1) expression, which subsequently increases calcium-activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω-Nitro-L-arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin-eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription-quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.
本研究假设富马酸和琥珀酸可能对妊娠高血压具有治疗作用。在怀孕期间，雌激素上调10-11易位蛋白1（TET1）的表达，随后增加钙激活钾通道亚基β1（KCNMB1）的表达。KCNMB1与高血压有关。据了解，富马酸和琥珀酸可抑制TET。因此，本研究调查了富马酸和琥珀酸是否对妊娠高血压具有治疗作用，以及这些作用是否由TET1和KCNMB1介导。将盐酸Nω-硝基-L-精氨酸甲酯注射到大鼠体内以建立妊娠高血压模型。将富马酸二甲酯（DMF）和琥珀酸给予大鼠以治疗妊娠高血压。大鼠分为五组：i）对照组；ii）模型组；iii）DMF组；iv）琥珀酸组；v）DMF +琥珀酸组。通过无创血压计监测血压，并使用尿蛋白试剂盒测定尿蛋白。通过苏木精-伊红染色检查胎盘病理。与对照组相比，模型组的尿蛋白和血压显著升高。对照组的胎盘细胞排列有序。然而，在模型组中，观察到胎盘的蜕膜细胞水肿和空泡变性，血管间膜明显增厚，有大量纤维蛋白沉积。这些结果表明成功建立了妊娠高血压模型。然而，与模型组相比，DMF组、琥珀酸组和DMF +琥珀酸组的尿蛋白、血压、水肿、空泡和纤维蛋白沉积明显减少。通过免疫组织化学分析、逆转录-定量聚合酶链反应和蛋白质印迹法评估胎盘中TET1和KCNMB1的mRNA和蛋白质水平。与对照组相比，模型组的TET1和KCNMB1水平显著升高。然而，与模型组相比，DMF组、琥珀酸组和DMF +琥珀酸组的表达水平明显下调。总之，富马酸和琥珀酸可能通过下调KCNMB1和TET1的表达来治疗妊娠高血压。
