Miyoshi Moe, Imakado Yasuhisa, Otani Lila, Kaji Misa, Aanzai Yuki, Sugimoto Naoya, Murakami Tetsuo, Fukuoka Masashi, Hohjoh Hirohiko, Jia Huijuan, Kato Hisanori
Health Nutrition Graduate School of Agricultural and Life Sciences University of Tokyo Tokyo Japan.
Department of Food Science and Nutrition Faculty of Agriculture Kinki University Nara Japan.
Food Sci Nutr. 2021 Jan 27;9(3):1452-1459. doi: 10.1002/fsn3.2113. eCollection 2021 Mar.
We previously demonstrated that protein restriction induced salt-sensitive hypertension and changed renal levels of angiotensin type 2 receptor (AT2R) in Stroke-Prone Spontaneously Hypertensive Rat (SHRSP). Here, we investigated if this characteristic alteration of AT2R is related to AT2R DNA methylation profiles.
First, we examined the relation between AT2R DNA methylation and its promoter activity in vitro. Luciferase assays revealed a negative correlation between these two variables. Next, we fed SHRSP dams and grand-dams a control 20% casein diet or a 9% casein diet during pregnancy. Adult offspring and grand-offspring were supplied either water or 1% saline solution for 2 weeks. Renal AT2R promoter DNA near the TATA-box was hypomethylated, mRNA expression was suppressed, and protein expression tended to be higher, in adult offspring of mothers fed a low casein diet. Moreover, adult grand-offspring exhibited high blood pressure after salt loading, along with suppressed transcription of AT2R mRNA and elevated translated protein.
Under a fetal environment of protein restriction, the increase in protein expression due to hypomethylation of the AT2R promoter region occurs as a response to increased salt sensitivity, and controlling this mechanism may be important for the prevention of hypertension.
我们之前证明，蛋白质限制会诱发盐敏感性高血压，并改变易患中风的自发性高血压大鼠（SHRSP）的肾脏血管紧张素2型受体（AT2R）水平。在此，我们研究了AT2R的这种特征性改变是否与AT2R DNA甲基化谱相关。
首先，我们在体外研究了AT2R DNA甲基化与其启动子活性之间的关系。荧光素酶测定显示这两个变量之间呈负相关。接下来，我们在妊娠期间给SHRSP母鼠和祖母代母鼠喂食对照20%酪蛋白饮食或9%酪蛋白饮食。成年子代和孙代子代分别饮用2周水或1%盐溶液。在喂食低酪蛋白饮食的母鼠的成年子代中，靠近TATA框的肾脏AT2R启动子DNA发生低甲基化，mRNA表达受到抑制，蛋白质表达倾向于更高。此外，成年孙代子代在盐负荷后出现高血压，同时AT2R mRNA转录受到抑制，翻译后的蛋白质升高。
在蛋白质限制的胎儿环境下，由于AT2R启动子区域低甲基化导致的蛋白质表达增加是对盐敏感性增加的一种反应，控制这一机制可能对预防高血压很重要。
