Doctor of Philosophy (PhD)
Salt-sensitive individuals have blood pressure that is unusually sensitive to salt intake. Because salt-sensitivity is a common disorder and may cause high blood pressure, it is a significant public health concern. All three epithelial Na+ channel (ENaC) subunits (a, b, and g) and the mineralocorticoid receptor (MR), a known regulator of ENaC, are expressed by vasopressin (VP) synthesizing magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. A growing body of evidence indicates that epithelial Na+ channels (ENaCs) in the hypothalamus play a significant role in the development of salt-sensitivity. My dissertation research tests the hypothesis that abnormal ENaC regulation occurs in VP neurons during salt-sensitive hypertension. To investigate this, I first used acute hypothalamic slices in an in vitro model to elucidate the ENaC regulatory mechanism present in the VP neurons of normotensive rats. Findings from this study demonstrated that aldosterone binds to the MR to directly interact with the promoter region of the γENaC gene to increase protein abundance in VP neurons, but aldosterone alone does not alter the ENaC-mediated current in VP neurons. To examine ENaC regulation during salt-sensitivity, Dahl salt-sensitive (Dahl-SS) and normotensive Sprague- Dawley (SD) rats were fed high salt diet to determine if any abnormal responses in the expression of ENaC subunits and MR occurred in the hypothalamus and kidney in response to a high dietary salt intake. Dietary salt intake caused a significant hypothalamic upregulation of gENaC in salt-sensitive animals and promoted proteolytic cleavage of the gENaC subunit. In contrast, the same dietary regimen caused significant downregulation of hypothalamic MR and kidney aENaC expression in normotensive animals. These results indicate a possible compensatory mechanism for salt-sensitive hypertension development present at the level of the hypothalamus of normotensive animals, which is not observed in salt-sensitive animals. Taken together, findings from my research suggest that high salt diet initiates a central pathway involving aldosterone-MR-ENaC in salt-sensitive animals to affect VP neuronal activity and contribute to hypertension development.
Mills, Natalie Jean, "Regulation of epithelial sodium channels in vasopressin neurons in the hypothalamus" (2018). LSU Doctoral Dissertations. 4667.