孕期高盐对胎肾RAS发育及高血压胎源性机制研究

Adverse intrauterine environment is closely linked to abnormal fetal development and increased risk of fetal original diseases. Over intake of salt may cause disorders in the heart, kidneys, and renin-angiotensin system (RAS), which may lead to body fluid imbalance and high blood pressure. However, information on effects of prenatal high salt diet(HSD) on renal RAS development and fetal original hypertension(FOH) is very limited. Our recent studies showed that prenatal HSD affected blood pressure, Na+ concentration and osmolality in ovine fetuses. Renal development is vulnerable to intrauterine environment.Kidney is a target organ for high blood pressure.This project hypothesis that renal RAS development and RAS-mediated body fluid balance as well as blood pressure could be affected by HSD, which may cause abnormal fetal development and FOH in the offspring. Therefore, this project will use our fetal models that were first established by our institute in China to study fetal functions in utero. We will determine impact of HSD on renal RAS development and the imprinting effects on programmed hypertension using in vivo, in vitro and molecular experiments,and test the effects of HSD on the expression of main RAS component(e.g. angiotensin II receptor) and DNA methylation related to gene regulatory regions in the kidney or renal arteries in the fetus and offspring. We'll focus on the underlying mechanism between the altered fetal renal RAS development and FOH induced by HSD during pregnancy. This project will provide new insight on HSD affected renal RAS development and fetal original hypertension, new information on early intervention of hypertension in fetal origins.

宫内不良环境与胎儿发育异常及胎源性疾病发病危险性增加密切相关。过量摄盐可使心，肾及肾素血管紧张素系统(RAS)功能紊乱致血压升高，肾发育易受宫内环境影响，肾是高血压靶器官。但孕期高盐(HSD)对胎肾RAS发育及与胎源性高血压(FOH)的关联研究鲜有报道。我们前期研究发现HSD可影响胎羊血压、血及尿中[Na+]及渗透压等。据此提出假说：HSD可影响肾RAS发育及其对血压和体液的调控，致胎儿发育异常并与子代FOH相关。为验证此，本项目利用国内首家建立的无应激状态下实时监测宫内胎羊多项功能研究平台，从整体、器官及分子水平研究HSD对肾RAS发育及其对血压调控的程序化效应，探讨子代肾脏或肾血管RAS主要成份(ATR等)表达及其基因调控区DNA甲基化改变，阐明HSD对胎肾RAS发育及与FOH关联机制。研究以独特的胎羊模型及表观遗传为新视点，为胎肾RAS发育与FOH胎源性机制研究和早期干预提供新思路。

宫内不良环境与胎儿发育异常及胎源性疾病发病危险性增加密切相关。过量摄盐可使心，肾及肾素血管紧张素系统(RAS)功能紊乱致血压升高，肾发育易受宫内环境影响，肾是高血压靶器官。但孕期高盐(HSD)对胎肾RAS发育及与胎源性高血压(FOH)的关联研究鲜有报道。我们的研究发现：1) 妊娠期给予母体高盐饮食（HSD），母胎及子代相关肾功能指标，血浆离子、渗透压以及血液循环中RAS 激素水平发生了一定改变；2)妊娠期给予母体HSD 对子代肾脏局部RAS功能有一定的影响；3) 妊娠期母体HSD 可导致子代肾脏血管发育及功能异常；4) 妊娠期母体HSD 使NO/cGMP/PKG信号通路的作用下调，使其对BKCa的作用减弱，从而降低血管的舒张调节功能，致使血管收缩反应相对增强。本项目从胚胎期到出生后的子代，研究了妊娠期母体高盐因素对胎肾RAS功能发育及其基因表达的影响；通过已建立的无应激条件下连续动态监测宫内胎羊多项功能的实验研究平台从整体实时观察母、胎各项指标的变换、从组织水平利用免疫组化方法观察组织形态学等的影响，并从细胞水平利用膜片钳技术研究血管平滑肌离子通道的调节等，及从分子水平利用分子生物学技术研究基因和蛋白表达水平的变化，探讨胎肾RAS发育与胎源性高血压发病危险间的关联及其机制，研究成果为胎肾RAS发育与FOH胎源性机制研究和早期干预提供新思路。