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

Abstract

The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.

Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney

“…Different models of developmental origins of adult disease are based on the exposure to low protein diet, excess of glucocorticoids, induced intrauterine growth restriction and postnatal blockade of the renin-angiotensin system. A common feature of these models is the development of renal damage and hypertension ( Zandi-Nejad et al, 2006 ; Hershkovitz et al, 2007 ; Ingelfinger and Nuyt, 2012 ; Stangenberg et al, 2015 ; Cuffe et al, 2016 ; Vieira-Rocha et al, 2019 ; DuPriest et al, 2020 ; Lamothe et al, 2020 ). Conversely, MatSep is a chronic behavioral stress model that induces subtle effects on the cardiovascular system in baseline/unstimulated conditions.…”

Whole transcriptome analysis of adrenal glands from prenatal glucocorticoid programmed hypertensive rodents

“…Despite evidence for GC mediated fetal programming of adult hypertension, the underlying molecular mechanisms have been largely uncharacterized. We and others have shown permanent molecular programming of genes involved in the catecholamine biosynthesis pathway in the adult adrenal glands of prenatal DEX exposed WKY rats 4 , 7 , 14 , 22 , 23 . Here, the programmed adrenal glands demonstrated modest upregulation of tyrosine hydroxylase , dopamine β-hydroxylase and phenylethanolamine N-methyl transferase .…”

Oxidative Stress Mediates the Fetal Programming of Hypertension by Glucocorticoids

“…Administration of Dex throughout the last trimester of pregnancy has been shown to alter the expression of catecholamine biosynthetic enzymes in adult offspring, leading to elevated plasma epinephrine and contributing to hypertensive programming [ 6 , 7 ]. Elevated plasma catecholamines have been linked to individuals with primary hypertension and likely plays a role in pathogenesis [ 8 ].…”

“…Glucocorticoids (GC) bind glucocorticoid receptors (GRs), forming a GR/GC complex which alters gene expression by binding glucocorticoid response elements (GRE) in gene promoter regions, including catecholamine biosynthetic enzymes [ 3 , 6 ]. Recent research has described changes in epigenetic regulators, such as HDACs and DNMTs, which appear to be implicated in programming [ 7 ]. Furthermore, a link between these epigenetic regulators and oxidative stress has been highlighted [ 7 ].…”

“…Recent research has described changes in epigenetic regulators, such as HDACs and DNMTs, which appear to be implicated in programming [ 7 ]. Furthermore, a link between these epigenetic regulators and oxidative stress has been highlighted [ 7 ].…”