Prenatal glucocorticoid exposure programs adrenal PNMT expression and adult hypertension

Abstract

Prenatal exposure to glucocorticoids (GCs) programs for hypertension later in life. The aim of the current study was to examine the impact of prenatal GC exposure on the postnatal regulation of the gene encoding for phenylethanolamine N-methyltransferase (PNMT), the enzyme involved in the biosynthesis of the catecholamine, epinephrine. PNMT has been linked to hypertension and is elevated in animal models of hypertension. Male offspring of Wistar-Kyoto dams treated with dexamethasone (DEX) developed elevated systolic, diastolic and mean arterial blood pressure compared to saline-treated controls. Plasma epinephrine levels were also elevated in adult rats exposed to DEX in utero. RT-PCR analysis revealed adrenal PNMT mRNA was higher in DEX exposed adult rats. This was associated with increased mRNA levels of transcriptional regulators of the PNMT gene: Egr-1, AP-2, and GR. Western blot analyses showed increased expression of PNMT protein, along with increased Egr-1 and GR in adult rats exposed to DEX in utero. Furthermore, gel mobility shift assays showed increased binding of Egr-1 and GR to DNA. These results suggest that increased PNMT gene expression via altered transcriptional activity is a possible mechanism by which prenatal exposure to elevated levels of GCs may program for hypertension later in life.

The Role of DNMT and HDACs in the Fetal Programming of Hypertension by Glucocorticoids

“…Pregnant females were separated and housed individually. They then received a subcutaneous injection of Dex (100 μg/kg/day in 4% ethanol/0.9% saline) or saline injec-tion (4% ethanol/0.9% saline) from GD -15-21 [2]. Following birth, offspring were weaned at 3 weeks of age and split into male and female groups.…”

“…The CODA-8 (Kent Scientific) noninvasive volume pressure recording tail-cuff BP system was employed to record BP measurements as performed previously [2]. Offspring were acclimated to the machine beginning at week 3 and measurements began at week 4 and ran until sacrifice at the end of week 14.…”

“…and sacrificed using decapitation [16]. Following decapitation, trunk blood was collected into EDTA-coated (10.8 mg) Vacutainer blood collection vials (Becton Dickinson, Franklin Lakes, NJ, USA), and tissues including adrenal glands were harvested and flash frozen on dry ice for future analysis [2].…”

“…GCs can stimulate tissue maturation and fetal development; however, in times of stress, excess production of maternal GCs can negatively impact the fetus, promoting premature tissue development and programing for disease [1]. As outlined in our previous paper, understanding how these changes in the fetal environment affect adult gene expression has been the key to unravelling the mechanisms involved in the fetal programming of hypertension [2]. Previous research has highlighted a role for ROS in programming; however, epigenetic modifications such as DNA methylation and histone acetylation are suspected to propagate these fetal insults to postnatal health.…”

Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions

“…[38] and augmented catecholamine release from adrenal glands [39] are involved in this mechanism. This is also related to the fetal programming of adult hypertension due to prenatal glucocorticoid exposure [40].…”