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

Abstract

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.

Nutrition and Developmental Origins of Kidney Disease

“…Regarding the developmental programming of CKD, altered methylation of angiotensin receptor 1 (AGTR1) has been shown to mediate the effect of prenatal famine exposure on eGFR decline across consecutive generations in humans [110]. In hypertensive rats, it was demonstrated that maternal protein deficiency in addition to a high-salt diet in the offspring resulted in hypertension that was associated with hypermethylation of prostaglandin E receptor 1 (PTGER1) and hypomethylation of angiotensin II receptor type 2 (AGTR2), respectively, in the kidney [111,112]. Further, AGTR1 hypomethylation in the blood was shown to predict CKD progression in HFDfed mice in adulthood [113], supporting an important role for the DNA methylation of angiotensin receptors and the developmental origin of CKD.…”

Postnatal nutrition environment reprograms renal DNA methylation patterns in offspring of maternal protein-restricted stroke-prone spontaneously hypertensive rats

“…Besides the above programming insults, maternal protein restriction has been established as a common developmental origin of hypertension. Studies in rodents have consistently reported that 6-9% protein restriction in pregnant mothers resulted in hypertension in adult offspring (14)(15)(16)(17). Previous studies led to several hypotheses about the underlying mechanisms, involving the suppression of the newborn renin-angiotensin system (18), impairment to nephrogenesis (19), triggering oxidative disruption in the medulla oblongata (20), or hindering the hypothalamic-pituitary-adrenal axis (21).…”

Effect of PLC-β1/CaM signaling pathway mediated by AT1R on the occurrence and development of hepatocellular carcinoma

“…Angiotensin II (Ang II) is an important vasoactive substance in human body, which can produce biological effects such as vasoconstriction, pro-inflammation, fibrosis and cell proliferation mediated by angiotensin II type 1 receptor (AT1R), while angiotensin II type 2 receptor (AT2R) may have completely opposite biological effects (Fig. 1 ) [ 6 – 8 ]. Ang II can be produced a large number in tumor tissues and up-regulate the expression of AT1R, further regulate the activities of signal proteins such as phospholipase-C (PLC), reactive oxygen species, nuclear factor-κappa B and nitric oxide, and affect the growth and metastasis of tumor cells [ 9 , 10 ].…”