Neurogenic hypertension : Revelations from genome-wide gene expression profiling
- Marques, Francine, Morris, Brian
- Authors: Marques, Francine , Morris, Brian
- Date: 2012
- Type: Text , Journal article
- Relation: Current Hypertension Reports Vol. 14, no. 6 (2012), p. 485-491
- Full Text: false
- Reviewed:
- Description: There is now good evidence for a role of the sympathetic nervous system in the etiology of essential hypertension in humans. Although genetic variation is expected to underlie the elevated sympathetic outflow in this complex polygenic condition, only limited information has emerged from classic molecular genetic studies. Recently, progress has been made in understanding neurogenic aspects by determination of global alterations in gene expression in key brain regions of animal models of neurogenic hypertension. Such genome-wide expression studies in the hypothalamus and brainstem support roles for factors such as neuronal nitric oxide synthase, inflammation and reactive oxygen species. A role for non-coding RNAs such as microRNAs, and epigenetic alterations await exploration. Ongoing novel approaches should provide a better understanding of the processes responsible for the increased sympathetic outflow in animal models, as well as essential hypertension in humans. Such information may lead to better therapies for neurogenic hypertension in humans. © Springer Science+Business Media, LLC 2012.
- Description: 2003010573
Epigenetic modifications in essential hypertension
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
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