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

Sujeenthar Tharmalingam,T C Tai,Alyssa Murray,Jeremy Lamothe,Sandhya Khurana

doi:10.1038/s41598-020-75652-y

Sujeenthar Tharmalingam, T C Tai + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-75652-y

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Abstract

Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. We have previously demonstrated that antenatal dexamethosone (DEX) administration in Wistar-Kyoto dams results in offspring with increased blood pressure coupled with elevated plasma epinephrine levels. In order to elucidate the molecular mechanisms responsible for prenatal DEX-mediated programming of hypertension, a whole-transcriptome analysis was performed on DEX programmed WKY male adrenal glands using the Rat Gene 2.0 microarray. Differential gene expression (DEG) analysis of DEX-exposed offspring compared with saline-treated controls revealed 142 significant DEGs (109 upregulated and 33 downregulated genes). DEG pathway enrichment analysis demonstrated that genes involved in circadian rhythm signaling were most robustly dysregulated. RT-qPCR analysis confirmed the increased expression of circadian genes Bmal1 and Npas2, while Per2, Per3, Cry2 and Bhlhe41 were significantly downregulated. In contrast, gene expression profiling of Spontaneously Hypertensive (SHR) rats, a genetic model of hypertension, demonstrated decreased expression of Bmal1 and Npas2, while Per1, Per2, Per3, Cry1, Cry2, Bhlhe41 and Csnk1D were all upregulated compared to naïve WKY controls. Taken together, this study establishes that glucocorticoid programmed adrenals have impaired circadian signaling and that changes in adrenal circadian rhythm may be an underlying molecular mechanism responsible for the development of hypertension.

Highlights

Prenatal glucocorticoid exposure is associated with the development of hypertension in adults
The full list of upregulated and down-regulated Differential gene expression (DEG) based on fold change is presented in Supplementary Table 2
We applied stringent transcriptomics parameters and identified 142 significant DEGs in DEX exposed adrenals compared to saline controls

Summary

Introduction

Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. Emerging evidence suggests that these stressors trigger molecular reconfiguration at the cellular level as a compensatory mechanism to survive the in-utero insult[4,7] This adaptation results in permanent molecular changes which increases the risk of developing disease later in life[8,9]. 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]. Identification of global gene expression alterations in the programmed adrenal glands will help elucidate the molecular mechanisms which contribute to the development of hypertension in adulthood

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