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| Endocrine Genetics |
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Hypertension and cardiovascular disease Cardiovascular disease is the largest cause of death in Australia, accounting for 40% of all fatalities. The underlying cause of much cardiovascular disease is hypertension, or high blood pressure. Hypertension is produced by a complicated mixture of genetic and environmental factors. One of the critical determinants of blood pressure control, and therefore of hypertension, is the body’s ability to handle salt (sodium). The most important factor in the control of salt balance is the steroid hormone aldosterone. Aldosterone is a steroid hormone secreted by the adrenal gland in response to a drop in blood pressure. It acts in the kidney and colon to increase the reabsorption of sodium from excreted fluids back into the body. Overstimulation of this system leads to hypertension. Aldosterone also has direct although undefined actions in the heart. A recent clinical trial found that blocking aldosterone action in the heart led to a 30% decrease in mortality of patients with heart failure. Despite the obvious importance of aldosterone in cardiovascular disease we still understand little of the basic molecular mechanisms of its action. This is the major focus of our work. Aldosterone acts by regulating the expression of target genes. One of the elusive goals in the field has been the identification of these genes. We have now identified, in the rat, four genes that are regulated directly by aldosterone. Two of these genes are subunits of the ‘epithelial sodium channel’ (ENaC). This channel is critical for pumping sodium back into the body. Another gene is the ‘serum and glucocorticoid regulated kinase’ (sgk). This enzyme has been shown to increase the activity of ENaC. The fourth gene is the ‘channel-inducing factor’ (CHIF). The function of this protein is unknown but it has homology to several proteins that modulate ion channels and pumps. Current studies aim to investigate in more detail how aldosterone acts to increase the expression of these genes. The search for new aldosterone-regulated genes is an ongoing interest in our laboratory. Aldosterone acts to control gene expression by binding to and activating the mineralocorticoid receptor (MR). The MR is a transcription factor that binds directly to the promoter regions of target genes. The MR antagonist spironolactone has been used for many years in the treatment of hypertension and may soon become important for treating heart failure patients. Unfortunately spironolactone has adverse side-effects due to its binding to other receptors. There is therefore a need for new, more specific, MR antagonists. The design of these drugs would be assisted by a better understanding of how ligands bind to the MR. We have discovered a region in the MR that is critical for the specificity of binding of both aldosterone and spironolactone. It is our aim identify the individual amino acids in the receptor that are responsible for binding specificity. To assist in this work we are collaborating with Dr Peter Colman and colleagues at the Walter and Eliza Hall Institute to determine the 3-dimensional structure of the receptor. They have modelled the structure of the ligand-binding domain of the MR based on related receptor structures. The mechanisms of action of the MR are complex and poorly understood. We know from the study of other steroid receptors that these proteins work by interacting with a range of coactivator proteins that enhance transcriptional initiation. We are currently using a variety of methods to identify and characterise coactivators that are important for MR function.
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