Wang Jing, Cui Jinghong, Chen Rui, Deng Youcai, Liao Xi, Wei Yanling, Li Xiaohui, Su Min, Yu Jianhua, Yi Ping
Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, China.
PLoS One. 2017 Jan 19;12(1):e0169206. doi: 10.1371/journal.pone.0169206. eCollection 2017.
Prenatal exposure to inflammation results in hypertension during adulthood but the mechanisms are not well understood. Maternal exposure to lipopolysaccharide (LPS) alters interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in the fetal environment. As reported in many recent studies, IL-6 regulates DNA methyltransferases (DNMTs) through the transcription factor friend leukemia virus integration 1 (Fli-1). The present study explores the role of intrarenal DNMTs during development of hypertension induced by prenatal exposure to LPS. Pregnant rats were randomly divided into four treatment groups: control, LPS, pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor), and the combination of LPS and PDTC. Expression of IL-6, Fli-1, TNF-α, DNMT1 and DNMT3B was significantly increased in the offspring of LPS-treated rats. Global DNA methylation level of renal cortex also increased dramatically in rat offspring of the LPS group. Prenatal PDTC administration reversed the increases in gene expression and global DNA methylation level. These findings suggest that prenatal exposure to LPS may result in changes of intrarenal DNMTs through the IL-6/Fli-1 pathway and TNF-α, which probably involves hypertension in offspring due to maternal exposure to inflammation.
孕期暴露于炎症会导致成年期高血压，但其机制尚不清楚。母体暴露于脂多糖（LPS）会改变胎儿环境中的白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平。正如最近许多研究所报道的，IL-6通过转录因子Friend白血病病毒整合1（Fli-1）调节DNA甲基转移酶（DNMTs）。本研究探讨了肾内DNMTs在孕期暴露于LPS诱导的高血压发展过程中的作用。将怀孕大鼠随机分为四个治疗组：对照组、LPS组、吡咯烷二硫代氨基甲酸盐（PDTC，一种NF-κB抑制剂）组以及LPS与PDTC联合组。在LPS处理的大鼠后代中，IL-6、Fli-1、TNF-α、DNMT1和DNMT3B的表达显著增加。LPS组大鼠后代肾皮质的整体DNA甲基化水平也显著升高。产前给予PDTC可逆转基因表达和整体DNA甲基化水平的升高。这些发现表明，孕期暴露于LPS可能通过IL-6/Fli-1途径和TNF-α导致肾内DNMTs发生变化，这可能与母体暴露于炎症导致后代高血压有关。
