Northern Ontario School of Medicine, Laurentian University, 935 Ramsey Lake Rd, Sudbury, ON, P3E 2C6, Canada.
Department of Biology, Laurentian University, Sudbury, ON, P3E 2C6, Canada.
Sci Rep. 2020 Oct 30;10(1):18755. doi: 10.1038/s41598-020-75652-y.
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.
产前糖皮质激素暴露与成年人高血压的发展有关。我们之前的研究表明，产前给予 Wistar-Kyoto 母鼠地塞米松（DEX）会导致后代血压升高，同时血浆肾上腺素水平升高。为了阐明产前 DEX 介导的高血压编程的分子机制，我们使用 Rat Gene 2.0 微阵列对 DEX 编程的 WKY 雄性肾上腺进行了全转录组分析。与生理盐水处理的对照组相比，DEX 暴露后代的差异基因表达（DEG）分析显示有 142 个显著 DEG（109 个上调和 33 个下调基因）。DEG 途径富集分析表明，参与昼夜节律信号的基因失调最为明显。RT-qPCR 分析证实了昼夜节律基因 Bmal1 和 Npas2 的表达增加，而 Per2、Per3、Cry2 和 Bhlhe41 的表达则显著下调。相比之下，高血压遗传模型自发性高血压（SHR）大鼠的基因表达谱分析表明，Bmal1 和 Npas2 的表达降低，而 Per1、Per2、Per3、Cry1、Cry2、Bhlhe41 和 Csnk1D 的表达均高于 naive WKY 对照组。综上所述，这项研究确立了糖皮质激素编程的肾上腺昼夜节律信号受损，而肾上腺昼夜节律的变化可能是高血压发展的潜在分子机制。
