25-30% of people have salt-sensitive blood pressure (BP), which is an independent risk factor for cardiovascular mortality. Mechanisms underpinning salt sensitive hypertension are not fully understood. However, our recent study (Evans et al, Circulation 2016) has suggested that abnormal glucocorticoid signalling can have a major contributory role in salt sensitivity. This project will systematically analyse hypothalamic-pituitary-adrenal axis function and glucocorticoid metabolism during the adaptation to high salt diets. We will use genetic engineering approaches to understand how high salt intake increases stress hormone production and how this leads to high blood pressure. Image Research Methods and Objectives This PhD project aims to exploit existing mouse models of salt-sensitivity induced by deleting the glucocorticoid-metabolizing enzyme 11BHSD2 in either the brain or the kidney. The project will first systematically analyse the effect of high dietary salt on the function of the hypothalamic-pituitary adrenal (HPA) axis in salt-sensitive knockouts and salt-resistant wild-types. Second, a combination of in vivo and ex vivo approaches will define how high salt diet induces hypertension in each of these models. Finally, the ability to selectively delete the glucocorticoid receptor will be exploited to define the key process through which increased glucocorticoid induces salt-sensitive hypertension. AIM 1: Systematic analysis of the HPA Axis High salt-intake increases circulating glucocorticoid, but it is not known how this occurs. Here we will systematically assess the effect of dietary salt on glucocorticoid production, glucocorticoid metabolism and the negative feedback mechanism that tightly regulates circulating glucocorticoids. Furthermore, we will define if salt-sensitive mice have enhanced feed-forward activation of the HPAA in response to stress. AIM 2: Renal/vascular function and blood pressure control Here we will first use radiotelemetry to confirm that hypertension is salt-sensitive in both the brain and kidney knockout of 11BHSD2. How high salt induces hypertension will be investigated looking at both vascular function and pressure natriuresis response. AIM 3: Does deletion of GR in the distal nephron rescue salt sensitivity? We plan to determine whether deletion of GR in distal tubule cells is protective against salt sensitivity. This research will provide important new understanding of abnormal glucocorticoid signalling and its relationship with salt sensitivity. This relationship can allow for the prediction of Metabolic Syndrome and cardiovascular risk. Principal Investigator, Co-Investigators, Other researchers Matthew Bailey, Hannah Costello, Ailsa Ralph, Neeraj Dhaun, Dawn Livingstone, Megan Holmes This article was published on 2024-03-19
