Salt-sensitive individuals have blood pressure that is unusually sensitive to salt intake (1). Salt-sensitivity increases the risk of death whether or nota person has high blood pressure. Furthermore, salt-sensitive persons are likely to develop high blood pressure as they age (2). Because salt sensitivity is common in the U.S., it is of significan public health concern. Current interventional approaches counter only the peripheral effects of salt sensitive hypertension, and the results are often unsatisfactory. Therefore, additional therapies that treat the cause of the disorder are needed. Although the mechanism of salt sensitivity is not well understood, a growing body of evidence suggests that it is caused by, at least partly, an abnormal regulation of the epithelial Na+ channels (ENaCs) in the brain. Both messengers and proteins for all three ENaC subunits were demonstrated in the rat brain including in vasopressin (VP) and oxytocin (OT) synthesizing magnocellular cells (MNCs) in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei (3). In addition, a known target for altered ENaC expression, the mineralocorticoid receptor (MR), is present in MNCs (3). VP and OT are released from the neurohypophysis into the general circulation. The secretion of VP increases in response to hyperosmolality, hypovolemia, and hypotension, and produces antidiuretic and pressor effects (4). Plasma OT increases in response to hypernatremia (5) and induces natriuresis (6, 7). Because, intracerebroventricular infusion of the ENaC blockers significantly attenuated the hypertension in animal models with salt-sensitive hypertension (8, 9), these findings strongly suggest that ENaC in MNCs play a significant role in the development of salt-sensitive hypertension. However, the role of ENaCs and their regulation in the brain is not well understood. Therefore, the overall objective of this proposed research is to characterize the functional significance of ENaCs in MNCs. Our recent study demonstrated that ENaC is a Na+-leak current modulating membrane potential and affecting the frequency action potentials evoked in MNCs (18). This implies that modulation of ENaC activity is a powerful means to modulate hormone secretion according to physiological demands. Based on results from my preliminary study, I hypothesize that dietary Na+ intake affects ENaCs activity that alters the patterns of action potentials in VP and OT MNCs which ultimately affect the secretion of these hormones. Therefore, abnormal regulation of ENaCs in these neurons contributes to the development of salt-sensitive hypertension. To address this hypothesis, we will employ the whole-cell patch clamp technique combined with immunocytochemistry, semi-quantitative RT-PCR and immunoblotting to determine: 1) how dietary salt intake affects both ENaC activity and the neuronal activity in MNCs;2) the regulatory roles of the mineralocorticoid aldosterone and VP on ENaC expression in MNCs;and 3) the activation mechanisms of ENaCs in MNCs. Results from this proposed project will provide critical information concerning central ENaC inhibition as a potential new target in the treatment of cardiovascular disease (10).
A growing body of evidence suggests that salt sensitive hypertension is caused by, at least partly, an abnormal regulation of amiloride-sensitive epithelial Na+ channels (ENaCs) in vasopressin and oxytocin hormone synthesizing neurons in the hypothalamus. While the brain ENaC may be a potential new target in the treatment of cardiovascular disease, the functional significance of ENaCs in vasopressin and oxytocin neurons is unknown. The research in this proposal will elucidate this critical mechanism, and will increase our ability to manage hypertension.
|Mills, Natalie J; Sharma, Kaustubh; Haque, Masudul et al. (2018) Aldosterone Mediated Regulation of Epithelial Sodium Channel (ENaC) Subunits in the Rat Hypothalamus. Neuroscience 390:278-292|
|Sharma, Kaustubh; Haque, Masudul; Guidry, Richard et al. (2017) Effect of dietary salt intake on epithelial Na+ channels (ENaC) in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus. J Physiol 595:5857-5874|
|Haque, M; Wilson, R; Sharma, K et al. (2015) Localisation of 11?-Hydroxysteroid Dehydrogenase Type 2 in Mineralocorticoid Receptor Expressing Magnocellular Neurosecretory Neurones of the Rat Supraoptic and Paraventricular Nuclei. J Neuroendocrinol 27:835-49|