Rac1在孕期脂多糖暴露对子代大鼠血压跨代遗传中的机制研究

Lipopolysaccharide (LPS) exposure during pregnancy causes increased blood pressure in the offspring (F1). We found the hypertensive-role of prenatal LPS exposure had a transgenerational inheritance effect, with inordinate natriuresis disturbance from offspring. By mRNA microarray analysis for kidney, we found that Ras-related C3 botulinum toxin substrate I (Rac1) was significantly increased both in F1 and F2, accompanied by inordinate elevated mineralocorticoid receptor (MR) nuclear translocation. When treated with Rac1-specific inhibitor, both natriuresis disturbance and elevated blood pressure were significantly relieved, suggesting that Rac1-MR signaling might be the key regulator of natriuresis disturbance and hypertensive effect. Further investigations revealed that the DNA methyltransferase 1 (DNMT1)　was down-regulated in kidney of the offspring, and its promoter had many methylation sites. Our previous research showed that prenatal LPS exposure will lead to an increased oxidative stress in offspring. Therefore, we presumed that decreased expression of DNMT1 is mediated by increased oxidative stress in kidney, subsequent hypomethylation in Rac1 promoter region and increased Rac1 expression. This hypomethylationcan be further passed to the offspring, which constantly activates Rac1-MR signaling pathway and subsequently natriuresis disturbance and lead to hypertension finally. The project aims to provide a new idea on mechanism of transgenerational inheritance of hypertension.

孕期脂多糖暴露可致大鼠子代高血压。我们发现该效应有跨代遗传现象，子代伴有尿钠排泄障碍，通过对F1和F2代肾脏mRNA芯片分析，发现Ras相关C3肉毒素底物I(Rac1)在F1和F2的肾脏表达均增加，伴有盐皮质激素受体(MR)入核增加。用Rac1特异抑制剂处理子代，发现尿钠代谢及血压均明显恢复。提示肾脏Rac1-MR信号轴的激活可能是高血压跨代遗传的主要机制。并且研究发现子代肾脏DNMT1表达降低，信息学预测发现Rac1启动子区域存在大量甲基化位点。结合本课题组前期发现孕期LPS暴露致子鼠ROS增强，而ROS可影响DNMT1表达，推测：孕期LPS刺激后ROS水平上升、DNMT1表达降低，致Rac1启动子区低甲基化和Rac1高表达；这种Rac1的低甲基化可稳定遗传给子代，持续激活子代Rac1-MR信号轴，致水钠代谢障碍，并最终导致高血压跨代遗传。该项目的研究为高血压跨代遗传的机制提供了新认识。

孕期脂多糖暴露可致大鼠子代高血压。我们发现该效应有跨代遗传现象，子代伴有尿钠排泄障碍，通过对F1和F2代肾脏mRNA芯片分析，发现Ras相关C3肉毒素底物I(Rac1)在F1和F2的肾脏表达均增加，伴有盐皮质激素受体(MR)胞浆减少，入核增加。用Rac1特异抑制剂处理子代，发现尿钠代谢及血压均明显恢复，且用MR拮抗剂安体舒通处理子代，发现尿钠代谢及血压也有明显恢复，推测肾脏Rac1-MR信号轴的激活是高血压跨代遗传的主要机制。另外，发现孕期LPS暴露可导致子代大鼠肾脏组蛋白H3K9me2表达下降， H3K9me2能够调控Rac1的表达。孕期LPS刺激后的子一代大鼠肾脏和血浆氧化应激指标（MDA）升高，抗氧化指标（SOD）下降。但是子二代和子三代没有明显差异。且用氧化应激抑制剂Temple处理子一代大鼠，能够有效降低其血压。因此，通过本研究发现孕期LPS刺激后ROS水平上升、H3K9me2表达下降，致Rac1启动子区低甲基化和Rac1高表达；这种Rac1的低甲基化可稳定遗传给子代，持续激活子代Rac1-MR信号轴，致水钠代谢障碍，并最终导致高血压跨代遗传。该项目的研究为高血压跨代遗传的机制提供了新认识。