Maternal protein restriction induces renal AT2R promoter hypomethylation in salt‐sensitive, hypertensive rats

SCOPE: We previously demonstrated that protein restriction in utero 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.